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<body xmlns="http://www.w3.org/1999/xhtml">Understanding the etiology of metastasis is very important in clinical perspective, since it is estimated that metastasis accounts for 90% of cancer patient mortality. Metastasis results from a sequence of multiple steps including invasion and migration. The early stages of metastasis are tightly controlled in normal cells and can be drastically affected by malignant mutations; therefore, they might constitute the principal determinants of the overall metastatic rate even if the later stages take long to occur. To elucidate the role of individual mutations or their combinations affecting the metastatic development, a logical model has been constructed that recapitulates published experimental results of known gene perturbations on local invasion and migration processes, and predict the effect of not yet experimentally assessed mutations. The model has been validated using experimental data on transcriptome dynamics following TGF-β-dependent induction of Epithelial to Mesenchymal Transition in lung cancer cell lines. A method to associate gene expression profiles with different stable state solutions of the logical model has been developed for that purpose. In addition, we have systematically predicted alleviating (masking) and synergistic pairwise genetic interactions between the genes composing the model with respect to the probability of acquiring the metastatic phenotype. We focused on several unexpected synergistic genetic interactions leading to theoretically very high metastasis probability. Among them, the synergistic combination of Notch overexpression and p53 deletion shows one of the strongest effects, which is in agreement with a recent published experiment in a mouse model of gut cancer. The mathematical model can recapitulate experimental mutations in both cell line and mouse models. Furthermore, the model predicts new gene perturbations that affect the early steps of metastasis underlying potential intervention points for innovative therapeutic strategies in oncology.</body>
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<vCard:EMAIL>birdgirl@arcticmail.com</vCard:EMAIL>
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<p>DNA damage</p></body>
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<body xmlns="http://www.w3.org/1999/xhtml">
<p>Extracellular Matrix</p></body>
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<notes>
<body xmlns="http://www.w3.org/1999/xhtml">
<p>Name: Vimentin</p><p>Gene Name: VIM</p><p>UNIPROT ID: P08670</p><p>Gene ID: 7431</p></body>
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<annotation>
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<notes>
<body xmlns="http://www.w3.org/1999/xhtml">
<p>Name: Mothers against decapentaplegic homolog 3</p><p>Gene Name: SMAD3</p><p>UNIPROT ID: P84022</p><p>Gene ID: 4088</p></body>
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<notes>
<body xmlns="http://www.w3.org/1999/xhtml">
<p>Name: Cyclin-dependent kinase inhibitor 1</p><p>Gene Name: CDKN1A</p><p>UNIPROT ID: P38936</p><p>Gene ID: 1026</p></body>
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<annotation>
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<notes>
<body xmlns="http://www.w3.org/1999/xhtml">
<p>Name: Zinc finger E-box-binding homeobox 1</p><p>Gene Name: ZEB1</p><p>UNIPROT ID: P37275</p><p>Gene ID: 6935</p></body>
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<annotation>
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<dcterms:W3CDTF>2017-02-01T14:57:59Z</dcterms:W3CDTF>
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<qual:qualitativeSpecies metaid="_4070c0d1-b32e-4381-adbe-40bc0bb34844" qual:compartment="cytosol" qual:constant="false" qual:id="S_6" qual:initialLevel="0" qual:maxLevel="1" qual:name="AKT1">
<notes>
<body xmlns="http://www.w3.org/1999/xhtml">
<p>Name: RAC-alpha serine/threonine-protein kinase</p><p>Gene Name: AKT1</p><p>UNIPROT ID: P31749</p><p>Gene ID: 207</p></body>
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<annotation>
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<dcterms:W3CDTF>2017-02-01T15:10:14Z</dcterms:W3CDTF>
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<qual:qualitativeSpecies metaid="_6334fe11-d163-4232-b3e4-9e1fed845e1c" qual:compartment="cytosol" qual:constant="false" qual:id="S_7" qual:initialLevel="0" qual:maxLevel="1" qual:name="EMT">
<notes>
<body xmlns="http://www.w3.org/1999/xhtml">
<p>Epithelial to Mesenchymal Transition</p><p>Morphological change epithelial cells undergo in order to gain motility.</p></body>
</notes>
<annotation>
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<notes>
<body xmlns="http://www.w3.org/1999/xhtml">
<p>Name: RAC-beta serine/threonine-protein kinase</p><p>Gene Name: AKT2</p><p>UNIPROT ID: P31751</p><p>Gene ID: 208</p></body>
</notes>
<annotation>
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<qual:qualitativeSpecies metaid="f5c8c884-59f7-44fc-85d9-8d8e31fdc9fa" qual:compartment="cytosol" qual:constant="false" qual:id="S_9" qual:initialLevel="0" qual:maxLevel="1" qual:name="Metastasis">
<notes>
<body xmlns="http://www.w3.org/1999/xhtml">
<p>Metastasis is the final stage of cancer development whereby secondary tumors in distant organs have formed.</p></body>
</notes>
<annotation>
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<notes>
<body xmlns="http://www.w3.org/1999/xhtml">
<p>Name: Catenin beta-1</p><p>Gene Name: CTNNB1</p><p>UNIPROT ID: P35222</p><p>Gene ID: 1499</p></body>
</notes>
<annotation>
<rdf:RDF xmlns:rdf="http://www.w3.org/1999/02/22-rdf-syntax-ns#" xmlns:dcterms="http://purl.org/dc/terms/">
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<notes>
<body xmlns="http://www.w3.org/1999/xhtml">
<p>Name: Cadherin-1</p><p>Gene Name: CDH1</p><p>UNIPROT ID: P12830</p><p>Gene ID: 999</p></body>
</notes>
<annotation>
<rdf:RDF xmlns:rdf="http://www.w3.org/1999/02/22-rdf-syntax-ns#" xmlns:dcterms="http://purl.org/dc/terms/">
<rdf:Description rdf:about="#_5906163e-8836-4bf8-b785-3c2d16c21a0e">
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<dcterms:W3CDTF>2017-02-01T15:07:34Z</dcterms:W3CDTF>
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<qual:qualitativeSpecies metaid="_62780883-7122-4581-8f7f-9a264d8e08de" qual:compartment="cytosol" qual:constant="false" qual:id="S_12" qual:initialLevel="0" qual:maxLevel="1" qual:name="SNAI1">
<notes>
<body xmlns="http://www.w3.org/1999/xhtml">
<p>Name: Zinc finger protein SNAI1</p><p>Gene Name: SNAI1</p><p>UNIPROT ID: O95863</p><p>Gene ID: 6615</p></body>
</notes>
<annotation>
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<dcterms:W3CDTF>2017-02-01T15:00:57Z</dcterms:W3CDTF>
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<notes>
<body xmlns="http://www.w3.org/1999/xhtml">
<p>Name: Tumor protein p73</p><p>Gene Name: TP73</p><p>UNIPROT ID: O15350</p><p>Gene ID: 7161</p></body>
</notes>
<annotation>
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<rdf:Description rdf:about="#_59812b5b-0ee4-46b9-ab4d-7b78dedaa9af">
<dcterms:modified rdf:parseType="Resource">
<dcterms:W3CDTF>2017-02-01T15:05:17Z</dcterms:W3CDTF>
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<qual:qualitativeSpecies metaid="acc435f2-61ad-4868-a405-98158cc33a62" qual:compartment="cytosol" qual:constant="false" qual:id="S_14" qual:initialLevel="0" qual:maxLevel="1" qual:name="CDH2">
<notes>
<body xmlns="http://www.w3.org/1999/xhtml">
<p>Name: Cadherin-2</p><p>Gene Name: CDH2</p><p>UNIPROT ID: P19022</p><p>Gene ID: 1000</p></body>
</notes>
<annotation>
<rdf:RDF xmlns:rdf="http://www.w3.org/1999/02/22-rdf-syntax-ns#" xmlns:dcterms="http://purl.org/dc/terms/">
<rdf:Description rdf:about="#acc435f2-61ad-4868-a405-98158cc33a62">
<dcterms:modified rdf:parseType="Resource">
<dcterms:W3CDTF>2017-02-01T15:08:31Z</dcterms:W3CDTF>
</dcterms:modified>
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</annotation>
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<qual:qualitativeSpecies metaid="_67519334-e369-43b3-b633-18659cd98e7b" qual:compartment="cytosol" qual:constant="false" qual:id="S_15" qual:initialLevel="0" qual:maxLevel="1" qual:name="ZEB2">
<notes>
<body xmlns="http://www.w3.org/1999/xhtml">
<p>Name: Zinc finger E-box-binding homeobox 2</p><p>Gene Name: ZEB2</p><p>UNIPROT ID: O60315</p><p>Gene ID: 9839</p></body>
</notes>
<annotation>
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<rdf:Description rdf:about="#_67519334-e369-43b3-b633-18659cd98e7b">
<dcterms:modified rdf:parseType="Resource">
<dcterms:W3CDTF>2017-02-01T15:05:17Z</dcterms:W3CDTF>
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<qual:qualitativeSpecies metaid="_637cffe4-0324-4778-8d97-8f8b83426632" qual:compartment="cytosol" qual:constant="false" qual:id="S_16" qual:initialLevel="0" qual:maxLevel="1" qual:name="GF">
<notes>
<body xmlns="http://www.w3.org/1999/xhtml">
<p>Growth Factors</p></body>
</notes>
<annotation>
<rdf:RDF xmlns:rdf="http://www.w3.org/1999/02/22-rdf-syntax-ns#" xmlns:dcterms="http://purl.org/dc/terms/">
<rdf:Description rdf:about="#_637cffe4-0324-4778-8d97-8f8b83426632">
<dcterms:modified rdf:parseType="Resource">
<dcterms:W3CDTF>2017-02-01T13:37:22Z</dcterms:W3CDTF>
</dcterms:modified>
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</annotation>
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<qual:qualitativeSpecies metaid="_46bda8b1-61b4-4c77-8f0c-4404ae3cb360" qual:compartment="cytosol" qual:constant="false" qual:id="S_17" qual:initialLevel="0" qual:maxLevel="1" qual:name="SNAI2">
<notes>
<body xmlns="http://www.w3.org/1999/xhtml">
<p>Name: Zinc finger protein SNAI2</p><p>Gene Name: SNAI2</p><p>UNIPROT ID: O43623</p><p>Gene ID: 6591</p></body>
</notes>
<annotation>
<rdf:RDF xmlns:rdf="http://www.w3.org/1999/02/22-rdf-syntax-ns#" xmlns:dcterms="http://purl.org/dc/terms/">
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<qual:qualitativeSpecies metaid="db65c673-b44f-410b-a6ac-1ab0920b0ddb" qual:compartment="cytosol" qual:constant="false" qual:id="S_18" qual:initialLevel="0" qual:maxLevel="1" qual:name="TWIST1">
<notes>
<body xmlns="http://www.w3.org/1999/xhtml">
<p>Name: Twist-related protein 1</p><p>Gene Name: TWIST1</p><p>UNIPROT ID: Q15672</p><p>Gene ID: 7291</p></body>
</notes>
<annotation>
<rdf:RDF xmlns:rdf="http://www.w3.org/1999/02/22-rdf-syntax-ns#" xmlns:dcterms="http://purl.org/dc/terms/">
<rdf:Description rdf:about="#db65c673-b44f-410b-a6ac-1ab0920b0ddb">
<dcterms:modified rdf:parseType="Resource">
<dcterms:W3CDTF>2017-02-01T15:00:57Z</dcterms:W3CDTF>
</dcterms:modified>
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</annotation>
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<qual:qualitativeSpecies metaid="edb2e245-7516-43aa-81dd-b20cadea25ea" qual:compartment="cytosol" qual:constant="false" qual:id="S_19" qual:initialLevel="0" qual:maxLevel="1" qual:name="Migration">
<notes>
<body xmlns="http://www.w3.org/1999/xhtml">
<p>Migration is a stage of cancer development whereby motile cancer cells spread to other parts of the body.</p></body>
</notes>
<annotation>
<rdf:RDF xmlns:rdf="http://www.w3.org/1999/02/22-rdf-syntax-ns#" xmlns:dcterms="http://purl.org/dc/terms/">
<rdf:Description rdf:about="#edb2e245-7516-43aa-81dd-b20cadea25ea">
<dcterms:modified rdf:parseType="Resource">
<dcterms:W3CDTF>2017-02-01T15:15:14Z</dcterms:W3CDTF>
</dcterms:modified>
</rdf:Description>
</rdf:RDF>
</annotation>
</qual:qualitativeSpecies>
<qual:qualitativeSpecies metaid="_71db6095-5374-4376-95ee-c5acacd41245" qual:compartment="cytosol" qual:constant="false" qual:id="S_20" qual:initialLevel="0" qual:maxLevel="1" qual:name="miR34">
<notes>
<body xmlns="http://www.w3.org/1999/xhtml">
<p>microRNA 34</p></body>
</notes>
<annotation>
<rdf:RDF xmlns:rdf="http://www.w3.org/1999/02/22-rdf-syntax-ns#" xmlns:dcterms="http://purl.org/dc/terms/">
<rdf:Description rdf:about="#_71db6095-5374-4376-95ee-c5acacd41245">
<dcterms:modified rdf:parseType="Resource">
<dcterms:W3CDTF>2017-02-01T15:05:17Z</dcterms:W3CDTF>
</dcterms:modified>
</rdf:Description>
</rdf:RDF>
</annotation>
</qual:qualitativeSpecies>
<qual:qualitativeSpecies metaid="ea28d6c9-b74d-4ac6-b093-e410b0296924" qual:compartment="cytosol" qual:constant="false" qual:id="S_21" qual:initialLevel="0" qual:maxLevel="1" qual:name="CellCycleArrest">
<notes>
<body xmlns="http://www.w3.org/1999/xhtml">
<p>This node represents when a cell has stopped progressing through the cell cycle.</p></body>
</notes>
<annotation>
<rdf:RDF xmlns:rdf="http://www.w3.org/1999/02/22-rdf-syntax-ns#" xmlns:dcterms="http://purl.org/dc/terms/">
<rdf:Description rdf:about="#ea28d6c9-b74d-4ac6-b093-e410b0296924">
<dcterms:modified rdf:parseType="Resource">
<dcterms:W3CDTF>2017-02-01T15:02:53Z</dcterms:W3CDTF>
</dcterms:modified>
</rdf:Description>
</rdf:RDF>
</annotation>
</qual:qualitativeSpecies>
<qual:qualitativeSpecies metaid="_551bfa37-c76c-4419-bea6-405fdf0cb392" qual:compartment="cytosol" qual:constant="false" qual:id="S_23" qual:initialLevel="0" qual:maxLevel="1" qual:name="DKK1">
<notes>
<body xmlns="http://www.w3.org/1999/xhtml">
<p>Name: Dickkopf-related protein 1</p><p>Gene Name: DKK1</p><p>UNIPROT ID: O94907</p><p>Gene ID: 22943</p></body>
</notes>
<annotation>
<rdf:RDF xmlns:rdf="http://www.w3.org/1999/02/22-rdf-syntax-ns#" xmlns:dcterms="http://purl.org/dc/terms/">
<rdf:Description rdf:about="#_551bfa37-c76c-4419-bea6-405fdf0cb392">
<dcterms:modified rdf:parseType="Resource">
<dcterms:W3CDTF>2017-02-01T13:34:36Z</dcterms:W3CDTF>
</dcterms:modified>
</rdf:Description>
</rdf:RDF>
</annotation>
</qual:qualitativeSpecies>
<qual:qualitativeSpecies metaid="bc36baa8-6963-4929-8770-ce1224975260" qual:compartment="cytosol" qual:constant="false" qual:id="S_25" qual:initialLevel="0" qual:maxLevel="1" qual:name="p63">
<notes>
<body xmlns="http://www.w3.org/1999/xhtml">
<p>Name: Tumor protein 63</p><p>Gene Name: TP63</p><p>UNIPROT ID: Q9H3D4</p><p>Gene ID: 8626</p></body>
</notes>
<annotation>
<rdf:RDF xmlns:rdf="http://www.w3.org/1999/02/22-rdf-syntax-ns#" xmlns:dcterms="http://purl.org/dc/terms/">
<rdf:Description rdf:about="#bc36baa8-6963-4929-8770-ce1224975260">
<dcterms:modified rdf:parseType="Resource">
<dcterms:W3CDTF>2017-02-01T15:10:14Z</dcterms:W3CDTF>
</dcterms:modified>
</rdf:Description>
</rdf:RDF>
</annotation>
</qual:qualitativeSpecies>
<qual:qualitativeSpecies metaid="_83fa016a-88f0-47ac-82fb-41b595fe1326" qual:compartment="cytosol" qual:constant="false" qual:id="S_26" qual:initialLevel="0" qual:maxLevel="1" qual:name="miR200">
<notes>
<body xmlns="http://www.w3.org/1999/xhtml">
<p>microRNA 200</p></body>
</notes>
<annotation>
<rdf:RDF xmlns:rdf="http://www.w3.org/1999/02/22-rdf-syntax-ns#" xmlns:dcterms="http://purl.org/dc/terms/">
<rdf:Description rdf:about="#_83fa016a-88f0-47ac-82fb-41b595fe1326">
<dcterms:modified rdf:parseType="Resource">
<dcterms:W3CDTF>2017-02-01T15:10:14Z</dcterms:W3CDTF>
</dcterms:modified>
</rdf:Description>
</rdf:RDF>
</annotation>
</qual:qualitativeSpecies>
<qual:qualitativeSpecies metaid="_8ede30a7-f4ae-4e94-afbf-ae903af29439" qual:compartment="cytosol" qual:constant="false" qual:id="S_27" qual:initialLevel="0" qual:maxLevel="1" qual:name="p53">
<notes>
<body xmlns="http://www.w3.org/1999/xhtml">
<p>Name: Cellular tumor antigen p53</p><p>Gene Name: TP53</p><p>UNIPROT ID: P04637</p><p>Gene ID: 7157</p></body>
</notes>
<annotation>
<rdf:RDF xmlns:rdf="http://www.w3.org/1999/02/22-rdf-syntax-ns#" xmlns:dcterms="http://purl.org/dc/terms/">
<rdf:Description rdf:about="#_8ede30a7-f4ae-4e94-afbf-ae903af29439">
<dcterms:modified rdf:parseType="Resource">
<dcterms:W3CDTF>2017-02-01T15:05:17Z</dcterms:W3CDTF>
</dcterms:modified>
</rdf:Description>
</rdf:RDF>
</annotation>
</qual:qualitativeSpecies>
<qual:qualitativeSpecies metaid="a23de29d-7984-430f-a401-39ebea403857" qual:compartment="cytosol" qual:constant="false" qual:id="S_28" qual:initialLevel="0" qual:maxLevel="1" qual:name="NICD">
<notes>
<body xmlns="http://www.w3.org/1999/xhtml">
<p>Intracellular domain of the Notch receptor</p><p>Name: Neurogenic locus notch homolog protein 1</p><p>Gene: NOTCH1</p><p>UniProtKB: P46531</p></body>
</notes>
<annotation>
<rdf:RDF xmlns:rdf="http://www.w3.org/1999/02/22-rdf-syntax-ns#" xmlns:dcterms="http://purl.org/dc/terms/">
<rdf:Description rdf:about="#a23de29d-7984-430f-a401-39ebea403857">
<dcterms:modified rdf:parseType="Resource">
<dcterms:W3CDTF>2017-02-01T15:00:57Z</dcterms:W3CDTF>
</dcterms:modified>
</rdf:Description>
</rdf:RDF>
</annotation>
</qual:qualitativeSpecies>
<qual:qualitativeSpecies metaid="_3df9fa59-e426-48c2-8a7e-cba20213baa4" qual:compartment="cytosol" qual:constant="false" qual:id="S_29" qual:initialLevel="0" qual:maxLevel="1" qual:name="TGFbeta">
<notes>
<body xmlns="http://www.w3.org/1999/xhtml">
<p>Name: Transforming growth factor beta-1</p><p>Gene Name: TGFB1</p><p>UNIPROT ID: P01137</p><p>Gene ID: 7040</p></body>
</notes>
<annotation>
<rdf:RDF xmlns:rdf="http://www.w3.org/1999/02/22-rdf-syntax-ns#" xmlns:dcterms="http://purl.org/dc/terms/">
<rdf:Description rdf:about="#_3df9fa59-e426-48c2-8a7e-cba20213baa4">
<dcterms:modified rdf:parseType="Resource">
<dcterms:W3CDTF>2017-02-01T14:53:27Z</dcterms:W3CDTF>
</dcterms:modified>
</rdf:Description>
</rdf:RDF>
</annotation>
</qual:qualitativeSpecies>
<qual:qualitativeSpecies metaid="_6db27b80-75b1-4c86-83dc-09b0918faf19" qual:compartment="cytosol" qual:constant="false" qual:id="S_30" qual:initialLevel="0" qual:maxLevel="1" qual:name="Apoptosis">
<notes>
<body xmlns="http://www.w3.org/1999/xhtml">
<p>Programmed cell death</p></body>
</notes>
<annotation>
<rdf:RDF xmlns:rdf="http://www.w3.org/1999/02/22-rdf-syntax-ns#" xmlns:dcterms="http://purl.org/dc/terms/">
<rdf:Description rdf:about="#_6db27b80-75b1-4c86-83dc-09b0918faf19">
<dcterms:modified rdf:parseType="Resource">
<dcterms:W3CDTF>2017-02-01T15:05:17Z</dcterms:W3CDTF>
</dcterms:modified>
</rdf:Description>
</rdf:RDF>
</annotation>
</qual:qualitativeSpecies>
<qual:qualitativeSpecies metaid="aa665907-455d-4f50-b73f-17383caa89e7" qual:compartment="cytosol" qual:constant="false" qual:id="S_31" qual:initialLevel="0" qual:maxLevel="1" qual:name="Invasion">
<notes>
<body xmlns="http://www.w3.org/1999/xhtml">
<p>Invasion is a stage of cancer development whereby motile cancer cells pass through the basement membrane and extracellular matrix.</p></body>
</notes>
<annotation>
<rdf:RDF xmlns:rdf="http://www.w3.org/1999/02/22-rdf-syntax-ns#" xmlns:dcterms="http://purl.org/dc/terms/">
<rdf:Description rdf:about="#aa665907-455d-4f50-b73f-17383caa89e7">
<dcterms:modified rdf:parseType="Resource">
<dcterms:W3CDTF>2017-02-01T15:15:00Z</dcterms:W3CDTF>
</dcterms:modified>
</rdf:Description>
</rdf:RDF>
</annotation>
</qual:qualitativeSpecies>
<qual:qualitativeSpecies metaid="ccd8182a-2b84-43d0-a131-71e765e25945" qual:compartment="cytosol" qual:constant="false" qual:id="S_32" qual:initialLevel="0" qual:maxLevel="1" qual:name="miR203">
<notes>
<body xmlns="http://www.w3.org/1999/xhtml">
<p>microRNA 203</p></body>
</notes>
<annotation>
<rdf:RDF xmlns:rdf="http://www.w3.org/1999/02/22-rdf-syntax-ns#" xmlns:dcterms="http://purl.org/dc/terms/">
<rdf:Description rdf:about="#ccd8182a-2b84-43d0-a131-71e765e25945">
<dcterms:modified rdf:parseType="Resource">
<dcterms:W3CDTF>2017-02-01T15:02:53Z</dcterms:W3CDTF>
</dcterms:modified>
</rdf:Description>
</rdf:RDF>
</annotation>
</qual:qualitativeSpecies>
</qual:listOfQualitativeSpecies>
<qual:listOfTransitions xmlns:qual="http://www.sbml.org/sbml/level3/version1/qual/version1">
<qual:transition qual:id="tr_S_1">
<notes>
<body xmlns="http://www.w3.org/1999/xhtml">
<p>SMAD, CDH2, GF, and NICD are all positive regulators of ERK. AKT1 inhibits ERK and expresses dominance over SMAD, CDH2, GF, and NICD.</p></body>
</notes>
<qual:listOfInputs>
<qual:input qual:id="tr_S_1_in_S_28" qual:qualitativeSpecies="S_28" qual:sign="positive" qual:thresholdLevel="1" qual:transitionEffect="none">
<notes>
<body xmlns="http://www.w3.org/1999/xhtml">
<p>NICD indirectly activates ERK. NICD activates HES1, which inhibits DUSP1/6, a negative regulator of ERK.</p></body>
</notes>
</qual:input>
<qual:input qual:id="tr_S_1_in_S_3" qual:qualitativeSpecies="S_3" qual:sign="positive" qual:thresholdLevel="1" qual:transitionEffect="none">
<notes>
<body xmlns="http://www.w3.org/1999/xhtml">
<p>SMAD activates ERK.</p></body>
</notes>
</qual:input>
<qual:input qual:id="tr_S_1_in_S_16" qual:qualitativeSpecies="S_16" qual:sign="positive" qual:thresholdLevel="1" qual:transitionEffect="none">
<notes>
<body xmlns="http://www.w3.org/1999/xhtml">
<p>Growth factors activate the MAPK signaling pathway.</p></body>
</notes>
</qual:input>
<qual:input qual:id="tr_S_1_in_S_6" qual:qualitativeSpecies="S_6" qual:sign="negative" qual:thresholdLevel="1" qual:transitionEffect="none">
<notes>
<body xmlns="http://www.w3.org/1999/xhtml">
<p>AKT1 inhibits ERK signalling.</p></body>
</notes>
</qual:input>
<qual:input qual:id="tr_S_1_in_S_14" qual:qualitativeSpecies="S_14" qual:sign="positive" qual:thresholdLevel="1" qual:transitionEffect="none">
<notes>
<body xmlns="http://www.w3.org/1999/xhtml">
<p>CDH2 activates ERK via FGFR polymerisation.</p></body>
</notes>
</qual:input>
</qual:listOfInputs>
<qual:listOfOutputs>
<qual:output qual:qualitativeSpecies="S_1" qual:transitionEffect="assignmentLevel"/>
</qual:listOfOutputs>
<qual:listOfFunctionTerms>
<qual:defaultTerm qual:resultLevel="0">
</qual:defaultTerm>
<qual:functionTerm qual:resultLevel="1">
<math xmlns="http://www.w3.org/1998/Math/MathML">
<apply>
<or/>
<apply>
<or/>
<apply>
<or/>
<apply>
<and/>
<apply>
<eq/>
<ci> S_14 </ci>
<cn type="integer"> 1 </cn>
</apply>
<apply>
<not/>
<apply>
<eq/>
<ci> S_6 </ci>
<cn type="integer"> 1 </cn>
</apply>
</apply>
</apply>
<apply>
<and/>
<apply>
<eq/>
<ci> S_28 </ci>
<cn type="integer"> 1 </cn>
</apply>
<apply>
<not/>
<apply>
<eq/>
<ci> S_6 </ci>
<cn type="integer"> 1 </cn>
</apply>
</apply>
</apply>
</apply>
<apply>
<and/>
<apply>
<eq/>
<ci> S_3 </ci>
<cn type="integer"> 1 </cn>
</apply>
<apply>
<not/>
<apply>
<eq/>
<ci> S_6 </ci>
<cn type="integer"> 1 </cn>
</apply>
</apply>
</apply>
</apply>
<apply>
<and/>
<apply>
<eq/>
<ci> S_16 </ci>
<cn type="integer"> 1 </cn>
</apply>
<apply>
<not/>
<apply>
<eq/>
<ci> S_6 </ci>
<cn type="integer"> 1 </cn>
</apply>
</apply>
</apply>
</apply>
</math>
</qual:functionTerm>
</qual:listOfFunctionTerms>
</qual:transition>
<qual:transition qual:id="tr_S_2">
<notes>
<body xmlns="http://www.w3.org/1999/xhtml">
<p>VIM is upregulated by both CTNNB1 and ZEB2.</p></body>
</notes>
<qual:listOfInputs>
<qual:input qual:id="tr_S_2_in_S_10" qual:qualitativeSpecies="S_10" qual:sign="positive" qual:thresholdLevel="1" qual:transitionEffect="none">
<notes>
<body xmlns="http://www.w3.org/1999/xhtml">
<p>CTNNB1 targets the VIM promoter to upregulate VIM expression.</p></body>
</notes>
</qual:input>
<qual:input qual:id="tr_S_2_in_S_15" qual:qualitativeSpecies="S_15" qual:sign="positive" qual:thresholdLevel="1" qual:transitionEffect="none">
<notes>
<body xmlns="http://www.w3.org/1999/xhtml">
<p>ZEB2 activates VIM gene transcription.</p></body>
</notes>
</qual:input>
</qual:listOfInputs>
<qual:listOfOutputs>
<qual:output qual:qualitativeSpecies="S_2" qual:transitionEffect="assignmentLevel"/>
</qual:listOfOutputs>
<qual:listOfFunctionTerms>
<qual:defaultTerm qual:resultLevel="0">
</qual:defaultTerm>
<qual:functionTerm qual:resultLevel="1">
<math xmlns="http://www.w3.org/1998/Math/MathML">
<apply>
<or/>
<apply>
<eq/>
<ci> S_15 </ci>
<cn type="integer"> 1 </cn>
</apply>
<apply>
<eq/>
<ci> S_10 </ci>
<cn type="integer"> 1 </cn>
</apply>
</apply>
</math>
</qual:functionTerm>
</qual:listOfFunctionTerms>
</qual:transition>
<qual:transition qual:id="tr_S_3">
<notes>
<body xmlns="http://www.w3.org/1999/xhtml">
<p>SMAD is activated by TGFbeta. SMAD is also inhibited by miR200 and miR203, which are dominant to TGFbeta.</p></body>
</notes>
<qual:listOfInputs>
<qual:input qual:id="tr_S_3_in_S_26" qual:qualitativeSpecies="S_26" qual:sign="negative" qual:thresholdLevel="1" qual:transitionEffect="none">
<notes>
<body xmlns="http://www.w3.org/1999/xhtml">
<p>miR200 inhibits SMAD2 and SMAD3.</p></body>
</notes>
</qual:input>
<qual:input qual:id="tr_S_3_in_S_29" qual:qualitativeSpecies="S_29" qual:sign="positive" qual:thresholdLevel="1" qual:transitionEffect="none">
<notes>
<body xmlns="http://www.w3.org/1999/xhtml">
<p>Binding of TGFbeta to its receptor actviates SMAD.</p></body>
</notes>
</qual:input>
<qual:input qual:id="tr_S_3_in_S_32" qual:qualitativeSpecies="S_32" qual:sign="negative" qual:thresholdLevel="1" qual:transitionEffect="none">
<notes>
<body xmlns="http://www.w3.org/1999/xhtml">
<p>A range of miRNAs have been found to target SMAD.</p></body>
</notes>
</qual:input>
</qual:listOfInputs>
<qual:listOfOutputs>
<qual:output qual:qualitativeSpecies="S_3" qual:transitionEffect="assignmentLevel"/>
</qual:listOfOutputs>
<qual:listOfFunctionTerms>
<qual:defaultTerm qual:resultLevel="0">
</qual:defaultTerm>
<qual:functionTerm qual:resultLevel="1">
<math xmlns="http://www.w3.org/1998/Math/MathML">
<apply>
<and/>
<apply>
<eq/>
<ci> S_29 </ci>
<cn type="integer"> 1 </cn>
</apply>
<apply>
<not/>
<apply>
<or/>
<apply>
<eq/>
<ci> S_26 </ci>
<cn type="integer"> 1 </cn>
</apply>
<apply>
<eq/>
<ci> S_32 </ci>
<cn type="integer"> 1 </cn>
</apply>
</apply>
</apply>
</apply>
</math>
</qual:functionTerm>
</qual:listOfFunctionTerms>
</qual:transition>
<qual:transition qual:id="tr_S_4">
<notes>
<body xmlns="http://www.w3.org/1999/xhtml">
<p>AKT2, p73, p63, and p53 all upregulate p21. SMAD also activates p21 in the presence of NICD. ERK and AKT1 are negative regulators of p21 which express dominance over SMAD, AKT2, p53, p63, and p73.</p></body>
</notes>
<qual:listOfInputs>
<qual:input qual:id="tr_S_4_in_S_1" qual:qualitativeSpecies="S_1" qual:sign="negative" qual:thresholdLevel="1" qual:transitionEffect="none">
<notes>
<body xmlns="http://www.w3.org/1999/xhtml">
<p>Inhibition of ERK leads tp p21 upregulation.</p></body>
</notes>
</qual:input>
<qual:input qual:id="tr_S_4_in_S_28" qual:qualitativeSpecies="S_28" qual:sign="positive" qual:thresholdLevel="1" qual:transitionEffect="none">
<notes>
<body xmlns="http://www.w3.org/1999/xhtml">
<p>In proliferating murine keratinocytes, Notch activation induces p21.</p><p>NICD enhances SMAD transcriptional activity.</p></body>
</notes>
</qual:input>
<qual:input qual:id="tr_S_4_in_S_3" qual:qualitativeSpecies="S_3" qual:sign="positive" qual:thresholdLevel="1" qual:transitionEffect="none">
<notes>
<body xmlns="http://www.w3.org/1999/xhtml">
<p>SMAD induces p21 transcription.</p></body>
</notes>
</qual:input>
<qual:input qual:id="tr_S_4_in_S_8" qual:qualitativeSpecies="S_8" qual:sign="positive" qual:thresholdLevel="1" qual:transitionEffect="none">
<notes>
<body xmlns="http://www.w3.org/1999/xhtml">
<p>AKT2 inhibits p21 by binding to the p21 promoter and by sequestering p21 in the nucleus in order to induce cell cycle arrest. (Studies performed using mouse myoblasts, human fibroblasts, and human myoblasts.)</p></body>
</notes>
</qual:input>
<qual:input qual:id="tr_S_4_in_S_6" qual:qualitativeSpecies="S_6" qual:sign="negative" qual:thresholdLevel="1" qual:transitionEffect="none">
<notes>
<body xmlns="http://www.w3.org/1999/xhtml">
<p>AKT1 phosphorylates p21 at Thr 145, which decreases p21 binding to the cyclin-dependent kinases Cdk2 and Cdk4.</p></body>
</notes>
</qual:input>
<qual:input qual:id="tr_S_4_in_S_25" qual:qualitativeSpecies="S_25" qual:sign="positive" qual:thresholdLevel="1" qual:transitionEffect="none">
<notes>
<body xmlns="http://www.w3.org/1999/xhtml">
<p>p63 is similar to p53 and has been found to regulate some of the same gene targets, such as p21.</p></body>
</notes>
</qual:input>
<qual:input qual:id="tr_S_4_in_S_27" qual:qualitativeSpecies="S_27" qual:sign="positive" qual:thresholdLevel="1" qual:transitionEffect="none">
<notes>
<body xmlns="http://www.w3.org/1999/xhtml">
<p>In human fibroblasts, p53 initiates cell cycle arrest by inducing the synthesis of p21.</p></body>
</notes>
</qual:input>
<qual:input qual:id="tr_S_4_in_S_13" qual:qualitativeSpecies="S_13" qual:sign="positive" qual:thresholdLevel="1" qual:transitionEffect="none">
<notes>
<body xmlns="http://www.w3.org/1999/xhtml">
<p>p73 can bind to the consensus DNA-binding motif and activate p53 gene targets, including p21.</p></body>
</notes>
</qual:input>
</qual:listOfInputs>
<qual:listOfOutputs>
<qual:output qual:qualitativeSpecies="S_4" qual:transitionEffect="assignmentLevel"/>
</qual:listOfOutputs>
<qual:listOfFunctionTerms>
<qual:defaultTerm qual:resultLevel="0">
</qual:defaultTerm>
<qual:functionTerm qual:resultLevel="1">
<math xmlns="http://www.w3.org/1998/Math/MathML">
<apply>
<or/>
<apply>
<or/>
<apply>
<or/>
<apply>
<or/>
<apply>
<and/>
<apply>
<and/>
<apply>
<eq/>
<ci> S_3 </ci>
<cn type="integer"> 1 </cn>
</apply>
<apply>
<eq/>
<ci> S_28 </ci>
<cn type="integer"> 1 </cn>
</apply>
</apply>
<apply>
<not/>
<apply>
<or/>
<apply>
<eq/>
<ci> S_1 </ci>
<cn type="integer"> 1 </cn>
</apply>
<apply>
<eq/>
<ci> S_6 </ci>
<cn type="integer"> 1 </cn>
</apply>
</apply>
</apply>
</apply>
<apply>
<and/>
<apply>
<eq/>
<ci> S_8 </ci>
<cn type="integer"> 1 </cn>
</apply>
<apply>
<not/>
<apply>
<or/>
<apply>
<eq/>
<ci> S_1 </ci>
<cn type="integer"> 1 </cn>
</apply>
<apply>
<eq/>
<ci> S_6 </ci>
<cn type="integer"> 1 </cn>
</apply>
</apply>
</apply>
</apply>
</apply>
<apply>
<and/>
<apply>
<eq/>
<ci> S_25 </ci>
<cn type="integer"> 1 </cn>
</apply>
<apply>
<not/>
<apply>
<or/>
<apply>
<eq/>
<ci> S_1 </ci>
<cn type="integer"> 1 </cn>
</apply>
<apply>
<eq/>
<ci> S_6 </ci>
<cn type="integer"> 1 </cn>
</apply>
</apply>
</apply>
</apply>
</apply>
<apply>
<and/>
<apply>
<eq/>
<ci> S_13 </ci>
<cn type="integer"> 1 </cn>
</apply>
<apply>
<not/>
<apply>
<or/>
<apply>
<eq/>
<ci> S_1 </ci>
<cn type="integer"> 1 </cn>
</apply>
<apply>
<eq/>
<ci> S_6 </ci>
<cn type="integer"> 1 </cn>
</apply>
</apply>
</apply>
</apply>
</apply>
<apply>
<and/>
<apply>
<eq/>
<ci> S_27 </ci>
<cn type="integer"> 1 </cn>
</apply>
<apply>
<not/>
<apply>
<or/>
<apply>
<eq/>
<ci> S_1 </ci>
<cn type="integer"> 1 </cn>
</apply>
<apply>
<eq/>
<ci> S_6 </ci>
<cn type="integer"> 1 </cn>
</apply>
</apply>
</apply>
</apply>
</apply>
</math>
</qual:functionTerm>
</qual:listOfFunctionTerms>
</qual:transition>
<qual:transition qual:id="tr_S_5">
<notes>
<body xmlns="http://www.w3.org/1999/xhtml">
<p>SNAI2, NICD, and CTNNB1 upregulate ZEB1. TWIST1 also activates ZEB1, but only in the presence of SNAI1. miR200 is a negative regulator of ZEB1 which expresses dominance over CTNNB1, NICD, SNAI2, and TWIST1.</p></body>
</notes>
<qual:listOfInputs>
<qual:input qual:id="tr_S_5_in_S_26" qual:qualitativeSpecies="S_26" qual:sign="negative" qual:thresholdLevel="1" qual:transitionEffect="none">
<notes>
<body xmlns="http://www.w3.org/1999/xhtml">
<p>miR00 is involved in a double-negative feedback loop with ZEB1.</p></body>
</notes>
</qual:input>
<qual:input qual:id="tr_S_5_in_S_10" qual:qualitativeSpecies="S_10" qual:sign="positive" qual:thresholdLevel="1" qual:transitionEffect="none">
<notes>
<body xmlns="http://www.w3.org/1999/xhtml">
<p>CTNNB1 binds to and activates the ZEB1 promoter.</p></body>
</notes>
</qual:input>
<qual:input qual:id="tr_S_5_in_S_12" qual:qualitativeSpecies="S_12" qual:sign="positive" qual:thresholdLevel="1" qual:transitionEffect="none">
<notes>
<body xmlns="http://www.w3.org/1999/xhtml">
<p>SNaI1 and TWIST1 work cooperatively to activate ZEB1 transcription. SNAI1 induces the rapid increase in TWIST protein. TWIST in turn is able to bind to the ZEB1 promoter.</p></body>
</notes>
</qual:input>
<qual:input qual:id="tr_S_5_in_S_28" qual:qualitativeSpecies="S_28" qual:sign="positive" qual:thresholdLevel="1" qual:transitionEffect="none">
<notes>
<body xmlns="http://www.w3.org/1999/xhtml">
<p>Over-expression of Notch-1 increased expression of ZEB1.</p></body>
</notes>
</qual:input>
<qual:input qual:id="tr_S_5_in_S_17" qual:qualitativeSpecies="S_17" qual:sign="positive" qual:thresholdLevel="1" qual:transitionEffect="none">
<notes>
<body xmlns="http://www.w3.org/1999/xhtml">
<p>SNAI2 binds to and activates the ZEB1 promoter.</p></body>
</notes>
</qual:input>
<qual:input qual:id="tr_S_5_in_S_18" qual:qualitativeSpecies="S_18" qual:sign="positive" qual:thresholdLevel="1" qual:transitionEffect="none">
<notes>
<body xmlns="http://www.w3.org/1999/xhtml">
<p>SNaI1 and TWIST1 work cooperatively to activate ZEB1 transcription. SNAI1 induces the rapid increase in TWIST protein. TWIST in turn is able to bind to the ZEB1 promoter.</p></body>
</notes>
</qual:input>
</qual:listOfInputs>
<qual:listOfOutputs>
<qual:output qual:qualitativeSpecies="S_5" qual:transitionEffect="assignmentLevel"/>
</qual:listOfOutputs>
<qual:listOfFunctionTerms>
<qual:defaultTerm qual:resultLevel="0">
</qual:defaultTerm>
<qual:functionTerm qual:resultLevel="1">
<math xmlns="http://www.w3.org/1998/Math/MathML">
<apply>
<or/>
<apply>
<or/>
<apply>
<or/>
<apply>
<and/>
<apply>
<eq/>
<ci> S_10 </ci>
<cn type="integer"> 1 </cn>
</apply>
<apply>
<not/>
<apply>
<eq/>
<ci> S_26 </ci>
<cn type="integer"> 1 </cn>
</apply>
</apply>
</apply>
<apply>
<and/>
<apply>
<eq/>
<ci> S_17 </ci>
<cn type="integer"> 1 </cn>
</apply>
<apply>
<not/>
<apply>
<eq/>
<ci> S_26 </ci>
<cn type="integer"> 1 </cn>
</apply>
</apply>
</apply>
</apply>
<apply>
<and/>
<apply>
<eq/>
<ci> S_28 </ci>
<cn type="integer"> 1 </cn>
</apply>
<apply>
<not/>
<apply>
<eq/>
<ci> S_26 </ci>
<cn type="integer"> 1 </cn>
</apply>
</apply>
</apply>
</apply>
<apply>
<and/>
<apply>
<and/>
<apply>
<eq/>
<ci> S_18 </ci>
<cn type="integer"> 1 </cn>
</apply>
<apply>
<eq/>
<ci> S_12 </ci>
<cn type="integer"> 1 </cn>
</apply>
</apply>
<apply>
<not/>
<apply>
<eq/>
<ci> S_26 </ci>
<cn type="integer"> 1 </cn>
</apply>
</apply>
</apply>
</apply>
</math>
</qual:functionTerm>
</qual:listOfFunctionTerms>
</qual:transition>
<qual:transition qual:id="tr_S_6">
<notes>
<body xmlns="http://www.w3.org/1999/xhtml">
<p>CTNNB1 activates AKT1 in the presence of either CDH2, GF, TGFbeta, or NICD. CDH1, p53, and miR34 are all negative regulators of AKT1 which express dominance over CTNNB1.</p></body>
</notes>
<qual:listOfInputs>
<qual:input qual:id="tr_S_6_in_S_10" qual:qualitativeSpecies="S_10" qual:sign="positive" qual:thresholdLevel="1" qual:transitionEffect="none">
<notes>
<body xmlns="http://www.w3.org/1999/xhtml">
<p>The CTNNB1/Tcf-4 complex activates AKT1 through Tcf-4 binding to the promoter.</p></body>
</notes>
</qual:input>
<qual:input qual:id="tr_S_6_in_S_29" qual:qualitativeSpecies="S_29" qual:sign="positive" qual:thresholdLevel="1" qual:transitionEffect="none">
<notes>
<body xmlns="http://www.w3.org/1999/xhtml">
<p>TGFbeta activates AKT1 through Mapk.</p></body>
</notes>
</qual:input>
<qual:input qual:id="tr_S_6_in_S_28" qual:qualitativeSpecies="S_28" qual:sign="positive" qual:thresholdLevel="1" qual:transitionEffect="none">
<notes>
<body xmlns="http://www.w3.org/1999/xhtml">
<p>Notch signalling activates HES, which inhibits PTEN, a negative regulator of AKT.</p></body>
</notes>
</qual:input>
<qual:input qual:id="tr_S_6_in_S_16" qual:qualitativeSpecies="S_16" qual:sign="positive" qual:thresholdLevel="1" qual:transitionEffect="none">
<notes>
<body xmlns="http://www.w3.org/1999/xhtml">
<p>GF induces AKT phosphorylation.</p></body>
</notes>
</qual:input>
<qual:input qual:id="tr_S_6_in_S_20" qual:qualitativeSpecies="S_20" qual:sign="negative" qual:thresholdLevel="1" qual:transitionEffect="none">
<notes>
<body xmlns="http://www.w3.org/1999/xhtml">
<p>Introduction of miR34 downregulated AKT1.</p></body>
</notes>
</qual:input>
<qual:input qual:id="tr_S_6_in_S_14" qual:qualitativeSpecies="S_14" qual:sign="positive" qual:thresholdLevel="1" qual:transitionEffect="none">
<notes>
<body xmlns="http://www.w3.org/1999/xhtml">
<p>CDH2 can activate FGFR, which leads to AKT1 activation.</p></body>
</notes>
</qual:input>
<qual:input qual:id="tr_S_6_in_S_11" qual:qualitativeSpecies="S_11" qual:sign="negative" qual:thresholdLevel="1" qual:transitionEffect="none">
<notes>
<body xmlns="http://www.w3.org/1999/xhtml">
<p>E-cadherin inhibits ligand binding to EGFR at high cell densities, leading to reduced AKT activation.</p></body>
</notes>
</qual:input>
<qual:input qual:id="tr_S_6_in_S_27" qual:qualitativeSpecies="S_27" qual:sign="negative" qual:thresholdLevel="1" qual:transitionEffect="none">
<notes>
<body xmlns="http://www.w3.org/1999/xhtml">
<p>p53 upregulates PTEN transcription, which in turn inhibits AKT activation.</p></body>
</notes>
</qual:input>
</qual:listOfInputs>
<qual:listOfOutputs>
<qual:output qual:qualitativeSpecies="S_6" qual:transitionEffect="assignmentLevel"/>
</qual:listOfOutputs>
<qual:listOfFunctionTerms>
<qual:defaultTerm qual:resultLevel="0">
</qual:defaultTerm>
<qual:functionTerm qual:resultLevel="1">
<math xmlns="http://www.w3.org/1998/Math/MathML">
<apply>
<and/>
<apply>
<and/>
<apply>
<eq/>
<ci> S_10 </ci>
<cn type="integer"> 1 </cn>
</apply>
<apply>
<or/>
<apply>
<or/>
<apply>
<or/>
<apply>
<eq/>
<ci> S_16 </ci>
<cn type="integer"> 1 </cn>
</apply>
<apply>
<eq/>
<ci> S_28 </ci>
<cn type="integer"> 1 </cn>
</apply>
</apply>
<apply>
<eq/>
<ci> S_29 </ci>
<cn type="integer"> 1 </cn>
</apply>
</apply>
<apply>
<eq/>
<ci> S_14 </ci>
<cn type="integer"> 1 </cn>
</apply>
</apply>
</apply>
<apply>
<not/>
<apply>
<or/>
<apply>
<or/>
<apply>
<eq/>
<ci> S_11 </ci>
<cn type="integer"> 1 </cn>
</apply>
<apply>
<eq/>
<ci> S_27 </ci>
<cn type="integer"> 1 </cn>
</apply>
</apply>
<apply>
<eq/>
<ci> S_20 </ci>
<cn type="integer"> 1 </cn>
</apply>
</apply>
</apply>
</apply>
</math>
</qual:functionTerm>
</qual:listOfFunctionTerms>
</qual:transition>
<qual:transition qual:id="tr_S_7">
<notes>
<body xmlns="http://www.w3.org/1999/xhtml">
<p>EMT is activated by CDH2 and inhibited by CDH1, which expresses dominance over CDH2.</p></body>
</notes>
<qual:listOfInputs>
<qual:input qual:id="tr_S_7_in_S_14" qual:qualitativeSpecies="S_14" qual:sign="positive" qual:thresholdLevel="1" qual:transitionEffect="none">
<notes>
<body xmlns="http://www.w3.org/1999/xhtml">
<p>The presence of mesenchymal markers (CDH2) activates EMT.</p></body>
</notes>
</qual:input>
<qual:input qual:id="tr_S_7_in_S_11" qual:qualitativeSpecies="S_11" qual:sign="negative" qual:thresholdLevel="1" qual:transitionEffect="none">
<notes>
<body xmlns="http://www.w3.org/1999/xhtml">
<p>The absence of epithelial markers (CDH1) activates EMT.</p></body>
</notes>
</qual:input>
</qual:listOfInputs>
<qual:listOfOutputs>
<qual:output qual:qualitativeSpecies="S_7" qual:transitionEffect="assignmentLevel"/>
</qual:listOfOutputs>
<qual:listOfFunctionTerms>
<qual:defaultTerm qual:resultLevel="0">
</qual:defaultTerm>
<qual:functionTerm qual:resultLevel="1">
<math xmlns="http://www.w3.org/1998/Math/MathML">
<apply>
<and/>
<apply>
<eq/>
<ci> S_14 </ci>
<cn type="integer"> 1 </cn>
</apply>
<apply>
<not/>
<apply>
<eq/>
<ci> S_11 </ci>
<cn type="integer"> 1 </cn>
</apply>
</apply>
</apply>
</math>
</qual:functionTerm>
</qual:listOfFunctionTerms>
</qual:transition>
<qual:transition qual:id="tr_S_8">
<notes>
<body xmlns="http://www.w3.org/1999/xhtml">
<p>When miR203, miR34, and p53 are all inactive, TWIST1 activates AKT2 in conjunction with either CDH2, GF, or TGFbeta.</p></body>
</notes>
<qual:listOfInputs>
<qual:input qual:id="tr_S_8_in_S_29" qual:qualitativeSpecies="S_29" qual:sign="positive" qual:thresholdLevel="1" qual:transitionEffect="none">
<notes>
<body xmlns="http://www.w3.org/1999/xhtml">
<p>TGFB association with its receptor and with the p85 subunit activates PI3K.</p></body>
</notes>
</qual:input>
<qual:input qual:id="tr_S_8_in_S_32" qual:qualitativeSpecies="S_32" qual:sign="negative" qual:thresholdLevel="1" qual:transitionEffect="none">
<notes>
<body xmlns="http://www.w3.org/1999/xhtml">
<p>miR203 inhibits AKT2 expression through mRNA degradation.</p></body>
</notes>
</qual:input>
<qual:input qual:id="tr_S_8_in_S_16" qual:qualitativeSpecies="S_16" qual:sign="positive" qual:thresholdLevel="1" qual:transitionEffect="none">
<notes>
<body xmlns="http://www.w3.org/1999/xhtml">
<p>GF induces AKT phosphorylation.</p></body>
</notes>
</qual:input>
<qual:input qual:id="tr_S_8_in_S_20" qual:qualitativeSpecies="S_20" qual:sign="negative" qual:thresholdLevel="1" qual:transitionEffect="none">
<notes>
<body xmlns="http://www.w3.org/1999/xhtml">
<p>miR34 inhibits AKT2 phosphorylation.</p></body>
</notes>
</qual:input>
<qual:input qual:id="tr_S_8_in_S_14" qual:qualitativeSpecies="S_14" qual:sign="positive" qual:thresholdLevel="1" qual:transitionEffect="none">
<notes>
<body xmlns="http://www.w3.org/1999/xhtml">
<p>CDH2 can activate FGFR, which leads to AKT1 activation.</p></body>
</notes>
</qual:input>
<qual:input qual:id="tr_S_8_in_S_18" qual:qualitativeSpecies="S_18" qual:sign="positive" qual:thresholdLevel="1" qual:transitionEffect="none">
<notes>
<body xmlns="http://www.w3.org/1999/xhtml">
<p>Twist induces AKT2 transcription.</p></body>
</notes>
</qual:input>
<qual:input qual:id="tr_S_8_in_S_27" qual:qualitativeSpecies="S_27" qual:sign="negative" qual:thresholdLevel="1" qual:transitionEffect="none">
<notes>
<body xmlns="http://www.w3.org/1999/xhtml">
<p>p53 inhibits AKT2 through activation of PTEN.</p></body>
</notes>
</qual:input>
</qual:listOfInputs>
<qual:listOfOutputs>
<qual:output qual:qualitativeSpecies="S_8" qual:transitionEffect="assignmentLevel"/>
</qual:listOfOutputs>
<qual:listOfFunctionTerms>
<qual:defaultTerm qual:resultLevel="0">
</qual:defaultTerm>
<qual:functionTerm qual:resultLevel="1">
<math xmlns="http://www.w3.org/1998/Math/MathML">
<apply>
<and/>
<apply>
<and/>
<apply>
<eq/>
<ci> S_18 </ci>
<cn type="integer"> 1 </cn>
</apply>
<apply>
<or/>
<apply>
<or/>
<apply>
<eq/>
<ci> S_29 </ci>
<cn type="integer"> 1 </cn>
</apply>
<apply>
<eq/>
<ci> S_16 </ci>
<cn type="integer"> 1 </cn>
</apply>
</apply>
<apply>
<eq/>
<ci> S_14 </ci>
<cn type="integer"> 1 </cn>
</apply>
</apply>
</apply>
<apply>
<and/>
<apply>
<and/>
<apply>
<not/>
<apply>
<eq/>
<ci> S_32 </ci>
<cn type="integer"> 1 </cn>
</apply>
</apply>
<apply>
<not/>
<apply>
<eq/>
<ci> S_20 </ci>
<cn type="integer"> 1 </cn>
</apply>
</apply>
</apply>
<apply>
<not/>
<apply>
<eq/>
<ci> S_27 </ci>
<cn type="integer"> 1 </cn>
</apply>
</apply>
</apply>
</apply>
</math>
</qual:functionTerm>
</qual:listOfFunctionTerms>
</qual:transition>
<qual:transition qual:id="tr_S_9">
<notes>
<body xmlns="http://www.w3.org/1999/xhtml">
<p>Migration is a positive regulator of Metastasis.</p></body>
</notes>
<qual:listOfInputs>
<qual:input qual:id="tr_S_9_in_S_19" qual:qualitativeSpecies="S_19" qual:sign="positive" qual:thresholdLevel="1" qual:transitionEffect="none">
<notes>
<body xmlns="http://www.w3.org/1999/xhtml">
<p>In order for secondary tumors to form at distant sites in the body, migration of cancer cells is required.</p></body>
</notes>
</qual:input>
</qual:listOfInputs>
<qual:listOfOutputs>
<qual:output qual:qualitativeSpecies="S_9" qual:transitionEffect="assignmentLevel"/>
</qual:listOfOutputs>
<qual:listOfFunctionTerms>
<qual:defaultTerm qual:resultLevel="0">
</qual:defaultTerm>
<qual:functionTerm qual:resultLevel="1">
<math xmlns="http://www.w3.org/1998/Math/MathML">
<apply>
<eq/>
<ci> S_19 </ci>
<cn type="integer"> 1 </cn>
</apply>
</math>
</qual:functionTerm>
</qual:listOfFunctionTerms>
</qual:transition>
<qual:transition qual:id="tr_S_10">
<notes>
<body xmlns="http://www.w3.org/1999/xhtml">
<p>DKK1, p53, AKT1, miR34, miR200, CDH1, CDH2 and p63 are all negative regulators of CTNNB1.</p></body>
</notes>
<qual:listOfInputs>
<qual:input qual:id="tr_S_10_in_S_26" qual:qualitativeSpecies="S_26" qual:sign="negative" qual:thresholdLevel="1" qual:transitionEffect="none">
<notes>
<body xmlns="http://www.w3.org/1999/xhtml">
<p>miR200 directly targets CTNBB1 mRNA.</p></body>
</notes>
</qual:input>
<qual:input qual:id="tr_S_10_in_S_23" qual:qualitativeSpecies="S_23" qual:sign="negative" qual:thresholdLevel="1" qual:transitionEffect="none">
<notes>
<body xmlns="http://www.w3.org/1999/xhtml">
<p>DKK1 is a negative regulator of Wnt signaling.</p></body>
</notes>
</qual:input>
<qual:input qual:id="tr_S_10_in_S_20" qual:qualitativeSpecies="S_20" qual:sign="negative" qual:thresholdLevel="1" qual:transitionEffect="none">
<notes>
<body xmlns="http://www.w3.org/1999/xhtml">
<p>miR34 binds to the 3′ untranslated regions of CTNBB1.</p></body>
</notes>
</qual:input>
<qual:input qual:id="tr_S_10_in_S_6" qual:qualitativeSpecies="S_6" qual:sign="negative" qual:thresholdLevel="1" qual:transitionEffect="none">
<notes>
<body xmlns="http://www.w3.org/1999/xhtml">
<p>AKT1 ativates Chibbv, which in turn phosphorylates CTNNB1 in the nucleus. This results in the export of CTNNB1 into the cytosol.</p></body>
</notes>
</qual:input>
<qual:input qual:id="tr_S_10_in_S_14" qual:qualitativeSpecies="S_14" qual:sign="negative" qual:thresholdLevel="1" qual:transitionEffect="none">
<notes>
<body xmlns="http://www.w3.org/1999/xhtml">
<p>CDH2 inhibits Wnt-signalling by forming a complex with CTNNB1.</p></body>
</notes>
</qual:input>
<qual:input qual:id="tr_S_10_in_S_25" qual:qualitativeSpecies="S_25" qual:sign="negative" qual:thresholdLevel="1" qual:transitionEffect="none">
<notes>
<body xmlns="http://www.w3.org/1999/xhtml">
<p>p63 inhibits CTNBB1 target gene expression.</p></body>
</notes>
</qual:input>
<qual:input qual:id="tr_S_10_in_S_11" qual:qualitativeSpecies="S_11" qual:sign="negative" qual:thresholdLevel="1" qual:transitionEffect="none">
<notes>
<body xmlns="http://www.w3.org/1999/xhtml">
<p>E-cadherin binds to and sequesters CTNNB1 at the cytoplasmic membrane, thereby preventing its nuclear translocation.</p></body>
</notes>
</qual:input>
<qual:input qual:id="tr_S_10_in_S_27" qual:qualitativeSpecies="S_27" qual:sign="negative" qual:thresholdLevel="1" qual:transitionEffect="none">
<notes>
<body xmlns="http://www.w3.org/1999/xhtml">
<p>p53 activates nuclear GSK3, which inhibits CTNBB1.</p></body>
</notes>
</qual:input>
</qual:listOfInputs>
<qual:listOfOutputs>
<qual:output qual:qualitativeSpecies="S_10" qual:transitionEffect="assignmentLevel"/>
</qual:listOfOutputs>
<qual:listOfFunctionTerms>
<qual:defaultTerm qual:resultLevel="0">
</qual:defaultTerm>
<qual:functionTerm qual:resultLevel="1">
<math xmlns="http://www.w3.org/1998/Math/MathML">
<apply>
<not/>
<apply>
<or/>
<apply>
<or/>
<apply>
<or/>
<apply>
<or/>
<apply>
<or/>
<apply>
<or/>
<apply>
<or/>
<apply>
<eq/>
<ci> S_25 </ci>
<cn type="integer"> 1 </cn>
</apply>
<apply>
<eq/>
<ci> S_6 </ci>
<cn type="integer"> 1 </cn>
</apply>
</apply>
<apply>
<eq/>
<ci> S_11 </ci>
<cn type="integer"> 1 </cn>
</apply>
</apply>
<apply>
<eq/>
<ci> S_23 </ci>
<cn type="integer"> 1 </cn>
</apply>
</apply>
<apply>
<eq/>
<ci> S_27 </ci>
<cn type="integer"> 1 </cn>
</apply>
</apply>
<apply>
<eq/>
<ci> S_26 </ci>
<cn type="integer"> 1 </cn>
</apply>
</apply>
<apply>
<eq/>
<ci> S_14 </ci>
<cn type="integer"> 1 </cn>
</apply>
</apply>
<apply>
<eq/>
<ci> S_20 </ci>
<cn type="integer"> 1 </cn>
</apply>
</apply>
</apply>
</math>
</qual:functionTerm>
</qual:listOfFunctionTerms>
</qual:transition>
<qual:transition qual:id="tr_S_11">
<notes>
<body xmlns="http://www.w3.org/1999/xhtml">
<p>AKT2, SNAI1, ZEB1, ZEB2, SNAI2, and TWIST1 all inhibit CDH1.</p></body>
</notes>
<qual:listOfInputs>
<qual:input qual:id="tr_S_11_in_S_5" qual:qualitativeSpecies="S_5" qual:sign="negative" qual:thresholdLevel="1" qual:transitionEffect="none">
<notes>
<body xmlns="http://www.w3.org/1999/xhtml">
<p>ZEB1 directly binds to the CDH1 promoter to repress its transcription.</p><p>SNAI2 activates ZEB1. The two proteins then cooperatively repress CDH1 expression.</p></body>
</notes>
</qual:input>
<qual:input qual:id="tr_S_11_in_S_12" qual:qualitativeSpecies="S_12" qual:sign="negative" qual:thresholdLevel="1" qual:transitionEffect="none">
<notes>
<body xmlns="http://www.w3.org/1999/xhtml">
<p>SNAI1 directly binds to the CDH1 promoter to repress its transcription.</p><p>Snai1 inhibits CDH1 through AKT2-mediated phosphorylation of histone H3 at Thr45.</p></body>
</notes>
</qual:input>
<qual:input qual:id="tr_S_11_in_S_8" qual:qualitativeSpecies="S_8" qual:sign="negative" qual:thresholdLevel="1" qual:transitionEffect="none">
<notes>
<body xmlns="http://www.w3.org/1999/xhtml">
<p>AKT2 induces gene expression of Dab2, which has been shown to decrease E-cadherin levels through an unknown mechanism.</p><p>Snai1 inhibits CDH1 through AKT2-mediated phosphorylation of histone H3 at Thr45.</p></body>
</notes>
</qual:input>
<qual:input qual:id="tr_S_11_in_S_17" qual:qualitativeSpecies="S_17" qual:sign="negative" qual:thresholdLevel="1" qual:transitionEffect="none">
<notes>
<body xmlns="http://www.w3.org/1999/xhtml">
<p>SNAI2 directly binds to the CDH1 promoter to repress its transcription.</p><p>SNAI2 activates ZEB1. The two proteins then cooperatively repress CDH1 expression.</p></body>
</notes>
</qual:input>
<qual:input qual:id="tr_S_11_in_S_18" qual:qualitativeSpecies="S_18" qual:sign="negative" qual:thresholdLevel="1" qual:transitionEffect="none">
<notes>
<body xmlns="http://www.w3.org/1999/xhtml">
<p>TWIST1 indirectly inhibits CDH1 by activating SNAI2.</p></body>
</notes>
</qual:input>
<qual:input qual:id="tr_S_11_in_S_15" qual:qualitativeSpecies="S_15" qual:sign="negative" qual:thresholdLevel="1" qual:transitionEffect="none">
<notes>
<body xmlns="http://www.w3.org/1999/xhtml">
<p>ZEB2 directly binds to the CDH1 promoter to repress its transcription.</p></body>
</notes>
</qual:input>
</qual:listOfInputs>
<qual:listOfOutputs>
<qual:output qual:qualitativeSpecies="S_11" qual:transitionEffect="assignmentLevel"/>
</qual:listOfOutputs>
<qual:listOfFunctionTerms>
<qual:defaultTerm qual:resultLevel="0">
</qual:defaultTerm>
<qual:functionTerm qual:resultLevel="1">
<math xmlns="http://www.w3.org/1998/Math/MathML">
<apply>
<not/>
<apply>
<or/>
<apply>
<or/>
<apply>
<or/>
<apply>
<or/>
<apply>
<or/>
<apply>
<eq/>
<ci> S_18 </ci>
<cn type="integer"> 1 </cn>
</apply>
<apply>
<eq/>
<ci> S_17 </ci>
<cn type="integer"> 1 </cn>
</apply>
</apply>
<apply>
<eq/>
<ci> S_15 </ci>
<cn type="integer"> 1 </cn>
</apply>
</apply>
<apply>
<eq/>
<ci> S_5 </ci>
<cn type="integer"> 1 </cn>
</apply>
</apply>
<apply>
<eq/>
<ci> S_8 </ci>
<cn type="integer"> 1 </cn>
</apply>
</apply>
<apply>
<eq/>
<ci> S_12 </ci>
<cn type="integer"> 1 </cn>
</apply>
</apply>
</apply>
</math>
</qual:functionTerm>
</qual:listOfFunctionTerms>
</qual:transition>
<qual:transition qual:id="tr_S_12">
<notes>
<body xmlns="http://www.w3.org/1999/xhtml">
<p>TWIST1 and NICD activate SNAI1. CTNNB1, p53, miR203, and miR34 are negative regulators of SNAI1 which hold dominance over NICD and TWIST1.</p></body>
</notes>
<qual:listOfInputs>
<qual:input qual:id="tr_S_12_in_S_10" qual:qualitativeSpecies="S_10" qual:sign="negative" qual:thresholdLevel="1" qual:transitionEffect="none">
<notes>
<body xmlns="http://www.w3.org/1999/xhtml">
<p>CTNNB1 inhibits SNAI1 by activating miR-30e.</p></body>
</notes>
</qual:input>
<qual:input qual:id="tr_S_12_in_S_32" qual:qualitativeSpecies="S_32" qual:sign="negative" qual:thresholdLevel="1" qual:transitionEffect="none">
<notes>
<body xmlns="http://www.w3.org/1999/xhtml">
<p>miR203 repressed endogenous SNAI1.</p></body>
</notes>
</qual:input>
<qual:input qual:id="tr_S_12_in_S_28" qual:qualitativeSpecies="S_28" qual:sign="positive" qual:thresholdLevel="1" qual:transitionEffect="none">
<notes>
<body xmlns="http://www.w3.org/1999/xhtml">
<p>NICD upregulates SNAI1 expression.</p></body>
</notes>
</qual:input>
<qual:input qual:id="tr_S_12_in_S_20" qual:qualitativeSpecies="S_20" qual:sign="negative" qual:thresholdLevel="1" qual:transitionEffect="none">
<notes>
<body xmlns="http://www.w3.org/1999/xhtml">
<p>Suppression of miR34 lead to an increase in SNAI1.</p></body>
</notes>
</qual:input>
<qual:input qual:id="tr_S_12_in_S_18" qual:qualitativeSpecies="S_18" qual:sign="positive" qual:thresholdLevel="1" qual:transitionEffect="none">
<notes>
<body xmlns="http://www.w3.org/1999/xhtml">
<p>TWIST1 upregulates SNAI1 expression.</p></body>
</notes>
</qual:input>
<qual:input qual:id="tr_S_12_in_S_27" qual:qualitativeSpecies="S_27" qual:sign="negative" qual:thresholdLevel="1" qual:transitionEffect="none">
<notes>
<body xmlns="http://www.w3.org/1999/xhtml">
<p>p53 induces the degradation of SAI1 via mdm2-mediated ubiquitination.</p></body>
</notes>
</qual:input>
</qual:listOfInputs>
<qual:listOfOutputs>
<qual:output qual:qualitativeSpecies="S_12" qual:transitionEffect="assignmentLevel"/>
</qual:listOfOutputs>
<qual:listOfFunctionTerms>
<qual:defaultTerm qual:resultLevel="0">
</qual:defaultTerm>
<qual:functionTerm qual:resultLevel="1">
<math xmlns="http://www.w3.org/1998/Math/MathML">
<apply>
<or/>
<apply>
<and/>
<apply>
<eq/>
<ci> S_18 </ci>
<cn type="integer"> 1 </cn>
</apply>
<apply>
<not/>
<apply>
<or/>
<apply>
<or/>
<apply>
<or/>
<apply>
<eq/>
<ci> S_27 </ci>
<cn type="integer"> 1 </cn>
</apply>
<apply>
<eq/>
<ci> S_32 </ci>
<cn type="integer"> 1 </cn>
</apply>
</apply>
<apply>
<eq/>
<ci> S_10 </ci>
<cn type="integer"> 1 </cn>
</apply>
</apply>
<apply>
<eq/>
<ci> S_20 </ci>
<cn type="integer"> 1 </cn>
</apply>
</apply>
</apply>
</apply>
<apply>
<and/>
<apply>
<eq/>
<ci> S_28 </ci>
<cn type="integer"> 1 </cn>
</apply>
<apply>
<not/>
<apply>
<or/>
<apply>
<or/>
<apply>
<or/>
<apply>
<eq/>
<ci> S_27 </ci>
<cn type="integer"> 1 </cn>
</apply>
<apply>
<eq/>
<ci> S_32 </ci>
<cn type="integer"> 1 </cn>
</apply>
</apply>
<apply>
<eq/>
<ci> S_10 </ci>
<cn type="integer"> 1 </cn>
</apply>
</apply>
<apply>
<eq/>
<ci> S_20 </ci>
<cn type="integer"> 1 </cn>
</apply>
</apply>
</apply>
</apply>
</apply>
</math>
</qual:functionTerm>
</qual:listOfFunctionTerms>
</qual:transition>
<qual:transition qual:id="tr_S_13">
<notes>
<body xmlns="http://www.w3.org/1999/xhtml">
<p>DNAdamage upregulates p73. AKT1, AKT2, p53, and ZEB1 are all inhibitors of p73 which express dominance over DNAdamage.</p></body>
</notes>
<qual:listOfInputs>
<qual:input qual:id="tr_S_13_in_S_5" qual:qualitativeSpecies="S_5" qual:sign="negative" qual:thresholdLevel="1" qual:transitionEffect="none">
<notes>
<body xmlns="http://www.w3.org/1999/xhtml">
<p>ZEB1 inhibits p73 expression.</p></body>
</notes>
</qual:input>
<qual:input qual:id="tr_S_13_in_S_8" qual:qualitativeSpecies="S_8" qual:sign="negative" qual:thresholdLevel="1" qual:transitionEffect="none">
<notes>
<body xmlns="http://www.w3.org/1999/xhtml">
<p>AKT2 inhibits p73 through MDM2-mediated degradation.</p></body>
</notes>
</qual:input>
<qual:input qual:id="tr_S_13_in_S_22" qual:qualitativeSpecies="S_22" qual:sign="positive" qual:thresholdLevel="1" qual:transitionEffect="none">
<notes>
<body xmlns="http://www.w3.org/1999/xhtml">
<p>p73 is important in regulating DNA repair systems after the introduction of DNA damage.</p></body>
</notes>
</qual:input>
<qual:input qual:id="tr_S_13_in_S_6" qual:qualitativeSpecies="S_6" qual:sign="negative" qual:thresholdLevel="1" qual:transitionEffect="none">
<notes>
<body xmlns="http://www.w3.org/1999/xhtml">
<p>AKT1 inhibits p73 through MDM2-mediated degradation.</p></body>
</notes>
</qual:input>
<qual:input qual:id="tr_S_13_in_S_27" qual:qualitativeSpecies="S_27" qual:sign="negative" qual:thresholdLevel="1" qual:transitionEffect="none">
<notes>
<body xmlns="http://www.w3.org/1999/xhtml">
<p>p53 inhibits p73 expression.</p></body>
</notes>
</qual:input>
</qual:listOfInputs>
<qual:listOfOutputs>
<qual:output qual:qualitativeSpecies="S_13" qual:transitionEffect="assignmentLevel"/>
</qual:listOfOutputs>
<qual:listOfFunctionTerms>
<qual:defaultTerm qual:resultLevel="0">
</qual:defaultTerm>
<qual:functionTerm qual:resultLevel="1">
<math xmlns="http://www.w3.org/1998/Math/MathML">
<apply>
<and/>
<apply>
<eq/>
<ci> S_22 </ci>
<cn type="integer"> 1 </cn>
</apply>
<apply>
<not/>
<apply>
<or/>
<apply>
<or/>
<apply>
<or/>
<apply>
<eq/>
<ci> S_6 </ci>
<cn type="integer"> 1 </cn>
</apply>
<apply>
<eq/>
<ci> S_27 </ci>
<cn type="integer"> 1 </cn>
</apply>
</apply>
<apply>
<eq/>
<ci> S_8 </ci>
<cn type="integer"> 1 </cn>
</apply>
</apply>
<apply>
<eq/>
<ci> S_5 </ci>
<cn type="integer"> 1 </cn>
</apply>
</apply>
</apply>
</apply>
</math>
</qual:functionTerm>
</qual:listOfFunctionTerms>
</qual:transition>
<qual:transition qual:id="tr_S_14">
<notes>
<body xmlns="http://www.w3.org/1999/xhtml">
<p>TWIST1 is a positive regulator of CDH2.</p></body>
</notes>
<qual:listOfInputs>
<qual:input qual:id="tr_S_14_in_S_18" qual:qualitativeSpecies="S_18" qual:sign="positive" qual:thresholdLevel="1" qual:transitionEffect="none">
<notes>
<body xmlns="http://www.w3.org/1999/xhtml">
<p>Twist1 binds to E-boxes in the CDH2 promoter and upregulates CDH2 transcription.</p></body>
</notes>
</qual:input>
</qual:listOfInputs>
<qual:listOfOutputs>
<qual:output qual:qualitativeSpecies="S_14" qual:transitionEffect="assignmentLevel"/>
</qual:listOfOutputs>
<qual:listOfFunctionTerms>
<qual:defaultTerm qual:resultLevel="0">
</qual:defaultTerm>
<qual:functionTerm qual:resultLevel="1">
<math xmlns="http://www.w3.org/1998/Math/MathML">
<apply>
<eq/>
<ci> S_18 </ci>
<cn type="integer"> 1 </cn>
</apply>
</math>
</qual:functionTerm>
</qual:listOfFunctionTerms>
</qual:transition>
<qual:transition qual:id="tr_S_15">
<notes>
<body xmlns="http://www.w3.org/1999/xhtml">
<p>SNAI2 activates ZEB2 in conjunction with TWIST1. SNAI1 and NICD also upregulate ZEB2. miR200 and miR203 are inhibitors of ZEB2 which express dominance over SNAI1, SNAI2, and NICD.</p></body>
</notes>
<qual:listOfInputs>
<qual:input qual:id="tr_S_15_in_S_26" qual:qualitativeSpecies="S_26" qual:sign="negative" qual:thresholdLevel="1" qual:transitionEffect="none">
<notes>
<body xmlns="http://www.w3.org/1999/xhtml">
<p>miR200 is involved in a double-negative feedback loop with ZEB1.</p></body>
</notes>
</qual:input>
<qual:input qual:id="tr_S_15_in_S_32" qual:qualitativeSpecies="S_32" qual:sign="negative" qual:thresholdLevel="1" qual:transitionEffect="none">
<notes>
<body xmlns="http://www.w3.org/1999/xhtml">
<p>miR203 targets and inhibits ZEB2.</p></body>
</notes>
</qual:input>
<qual:input qual:id="tr_S_15_in_S_12" qual:qualitativeSpecies="S_12" qual:sign="positive" qual:thresholdLevel="1" qual:transitionEffect="none">
<notes>
<body xmlns="http://www.w3.org/1999/xhtml">
<p>SNAI1 upregulates ZEB2 expression by preventing the processing of a large intron located in ZEB2's 5′-untranslated region.</p></body>
</notes>
</qual:input>
<qual:input qual:id="tr_S_15_in_S_28" qual:qualitativeSpecies="S_28" qual:sign="positive" qual:thresholdLevel="1" qual:transitionEffect="none">
<notes>
<body xmlns="http://www.w3.org/1999/xhtml">
<p>Over-expression of Notch-1 increased expression of ZEB1.</p></body>
</notes>
</qual:input>
<qual:input qual:id="tr_S_15_in_S_17" qual:qualitativeSpecies="S_17" qual:sign="positive" qual:thresholdLevel="1" qual:transitionEffect="none">
<notes>
<body xmlns="http://www.w3.org/1999/xhtml">
<p>TWIST1 and SNAI2 work cooperatively to activate ZEB2 transcription.</p></body>
</notes>
</qual:input>
<qual:input qual:id="tr_S_15_in_S_18" qual:qualitativeSpecies="S_18" qual:sign="positive" qual:thresholdLevel="1" qual:transitionEffect="none">
<notes>
<body xmlns="http://www.w3.org/1999/xhtml">
<p>TWIST1 and SNAI2 work cooperatively to activate ZEB2 transcription.</p></body>
</notes>
</qual:input>
</qual:listOfInputs>
<qual:listOfOutputs>
<qual:output qual:qualitativeSpecies="S_15" qual:transitionEffect="assignmentLevel"/>
</qual:listOfOutputs>
<qual:listOfFunctionTerms>
<qual:defaultTerm qual:resultLevel="0">
</qual:defaultTerm>
<qual:functionTerm qual:resultLevel="1">
<math xmlns="http://www.w3.org/1998/Math/MathML">
<apply>
<or/>
<apply>
<or/>
<apply>
<and/>
<apply>
<eq/>
<ci> S_28 </ci>
<cn type="integer"> 1 </cn>
</apply>
<apply>
<not/>
<apply>
<or/>
<apply>
<eq/>
<ci> S_32 </ci>
<cn type="integer"> 1 </cn>
</apply>
<apply>
<eq/>
<ci> S_26 </ci>
<cn type="integer"> 1 </cn>
</apply>
</apply>
</apply>
</apply>
<apply>
<and/>
<apply>
<eq/>
<ci> S_12 </ci>
<cn type="integer"> 1 </cn>
</apply>
<apply>
<not/>
<apply>
<or/>
<apply>
<eq/>
<ci> S_32 </ci>
<cn type="integer"> 1 </cn>
</apply>
<apply>
<eq/>
<ci> S_26 </ci>
<cn type="integer"> 1 </cn>
</apply>
</apply>
</apply>
</apply>
</apply>
<apply>
<and/>
<apply>
<and/>
<apply>
<eq/>
<ci> S_17 </ci>
<cn type="integer"> 1 </cn>
</apply>
<apply>
<eq/>
<ci> S_18 </ci>
<cn type="integer"> 1 </cn>
</apply>
</apply>
<apply>
<not/>
<apply>
<or/>
<apply>
<eq/>
<ci> S_32 </ci>
<cn type="integer"> 1 </cn>
</apply>
<apply>
<eq/>
<ci> S_26 </ci>
<cn type="integer"> 1 </cn>
</apply>
</apply>
</apply>
</apply>
</apply>
</math>
</qual:functionTerm>
</qual:listOfFunctionTerms>
</qual:transition>
<qual:transition qual:id="tr_S_16">
<notes>
<body xmlns="http://www.w3.org/1999/xhtml">
<p>GF and CDH2 activate GF. CDH1 is a negative regulator of GF which expresses dominance over both GF and CDH2.</p></body>
</notes>
<qual:listOfInputs>
<qual:input qual:id="tr_S_16_in_S_16" qual:qualitativeSpecies="S_16" qual:sign="positive" qual:thresholdLevel="1" qual:transitionEffect="none">
<notes>
<body xmlns="http://www.w3.org/1999/xhtml">
<p>The cell cycle can produce ligands and thus activate the receptor tyrosine kinase family of receptors that eventually the cell to produce growth factor.</p></body>
</notes>
</qual:input>
<qual:input qual:id="tr_S_16_in_S_14" qual:qualitativeSpecies="S_14" qual:sign="positive" qual:thresholdLevel="1" qual:transitionEffect="none">
<notes>
<body xmlns="http://www.w3.org/1999/xhtml">
<p>N-cadherin caused the upregulation of fibroblast growth factor receptor expression.</p></body>
</notes>
</qual:input>
<qual:input qual:id="tr_S_16_in_S_11" qual:qualitativeSpecies="S_11" qual:sign="negative" qual:thresholdLevel="1" qual:transitionEffect="none">
<notes>
<body xmlns="http://www.w3.org/1999/xhtml">
<p>E-cadherin blocks GF signaling.</p></body>
</notes>
</qual:input>
</qual:listOfInputs>
<qual:listOfOutputs>
<qual:output qual:qualitativeSpecies="S_16" qual:transitionEffect="assignmentLevel"/>
</qual:listOfOutputs>
<qual:listOfFunctionTerms>
<qual:defaultTerm qual:resultLevel="0">
</qual:defaultTerm>
<qual:functionTerm qual:resultLevel="1">
<math xmlns="http://www.w3.org/1998/Math/MathML">
<apply>
<or/>
<apply>
<and/>
<apply>
<eq/>
<ci> S_16 </ci>
<cn type="integer"> 1 </cn>
</apply>
<apply>
<not/>
<apply>
<eq/>
<ci> S_11 </ci>
<cn type="integer"> 1 </cn>
</apply>
</apply>
</apply>
<apply>
<and/>
<apply>
<eq/>
<ci> S_14 </ci>
<cn type="integer"> 1 </cn>
</apply>
<apply>
<not/>
<apply>
<eq/>
<ci> S_11 </ci>
<cn type="integer"> 1 </cn>
</apply>
</apply>
</apply>
</apply>
</math>
</qual:functionTerm>
</qual:listOfFunctionTerms>
</qual:transition>
<qual:transition qual:id="tr_S_17">
<notes>
<body xmlns="http://www.w3.org/1999/xhtml">
<p>CTNNB1, NICD, and TWIST1 activate SNAI2. p53, miR203, and miR200 are inhibitors of SNAI2 which express dominance over TWIST1, NICD, and CTNNB1.</p></body>
</notes>
<qual:listOfInputs>
<qual:input qual:id="tr_S_17_in_S_10" qual:qualitativeSpecies="S_10" qual:sign="positive" qual:thresholdLevel="1" qual:transitionEffect="none">
<notes>
<body xmlns="http://www.w3.org/1999/xhtml">
<p>The SNAI2 promoter contains cis-regulatory sequences which respond to CTNNB1 signaling.</p></body>
</notes>
</qual:input>
<qual:input qual:id="tr_S_17_in_S_26" qual:qualitativeSpecies="S_26" qual:sign="negative" qual:thresholdLevel="1" qual:transitionEffect="none">
<notes>
<body xmlns="http://www.w3.org/1999/xhtml">
<p>SNAI2 is a target of miR200.</p></body>
</notes>
</qual:input>
<qual:input qual:id="tr_S_17_in_S_32" qual:qualitativeSpecies="S_32" qual:sign="negative" qual:thresholdLevel="1" qual:transitionEffect="none">
<notes>
<body xmlns="http://www.w3.org/1999/xhtml">
<p>miR203 targets SNAI2.</p></body>
</notes>
</qual:input>
<qual:input qual:id="tr_S_17_in_S_28" qual:qualitativeSpecies="S_28" qual:sign="positive" qual:thresholdLevel="1" qual:transitionEffect="none">
<notes>
<body xmlns="http://www.w3.org/1999/xhtml">
<p>SNAI2 is a direct target of Notch signaling.</p></body>
</notes>
</qual:input>
<qual:input qual:id="tr_S_17_in_S_18" qual:qualitativeSpecies="S_18" qual:sign="positive" qual:thresholdLevel="1" qual:transitionEffect="none">
<notes>
<body xmlns="http://www.w3.org/1999/xhtml">
<p>TWIST1 induces SNAI1 transcription.</p></body>
</notes>
</qual:input>
<qual:input qual:id="tr_S_17_in_S_27" qual:qualitativeSpecies="S_27" qual:sign="negative" qual:thresholdLevel="1" qual:transitionEffect="none">
<notes>
<body xmlns="http://www.w3.org/1999/xhtml">
<p>p53 induces the degradation of SAI1 via mdm2-mediated ubiquitination.</p></body>
</notes>
</qual:input>
</qual:listOfInputs>
<qual:listOfOutputs>
<qual:output qual:qualitativeSpecies="S_17" qual:transitionEffect="assignmentLevel"/>
</qual:listOfOutputs>
<qual:listOfFunctionTerms>
<qual:defaultTerm qual:resultLevel="0">
</qual:defaultTerm>
<qual:functionTerm qual:resultLevel="1">
<math xmlns="http://www.w3.org/1998/Math/MathML">
<apply>
<or/>
<apply>
<or/>
<apply>
<and/>
<apply>
<eq/>
<ci> S_10 </ci>
<cn type="integer"> 1 </cn>
</apply>
<apply>
<not/>
<apply>
<or/>
<apply>
<or/>
<apply>
<eq/>
<ci> S_32 </ci>
<cn type="integer"> 1 </cn>
</apply>
<apply>
<eq/>
<ci> S_27 </ci>
<cn type="integer"> 1 </cn>
</apply>
</apply>
<apply>
<eq/>
<ci> S_26 </ci>
<cn type="integer"> 1 </cn>
</apply>
</apply>
</apply>
</apply>
<apply>
<and/>
<apply>
<eq/>
<ci> S_28 </ci>
<cn type="integer"> 1 </cn>
</apply>
<apply>
<not/>
<apply>
<or/>
<apply>
<or/>
<apply>
<eq/>
<ci> S_32 </ci>
<cn type="integer"> 1 </cn>
</apply>
<apply>
<eq/>
<ci> S_27 </ci>
<cn type="integer"> 1 </cn>
</apply>
</apply>
<apply>
<eq/>
<ci> S_26 </ci>
<cn type="integer"> 1 </cn>
</apply>
</apply>
</apply>
</apply>
</apply>
<apply>
<and/>
<apply>
<eq/>
<ci> S_18 </ci>
<cn type="integer"> 1 </cn>
</apply>
<apply>
<not/>
<apply>
<or/>
<apply>
<or/>
<apply>
<eq/>
<ci> S_32 </ci>
<cn type="integer"> 1 </cn>
</apply>
<apply>
<eq/>
<ci> S_27 </ci>
<cn type="integer"> 1 </cn>
</apply>
</apply>
<apply>
<eq/>
<ci> S_26 </ci>
<cn type="integer"> 1 </cn>
</apply>
</apply>
</apply>
</apply>
</apply>
</math>
</qual:functionTerm>
</qual:listOfFunctionTerms>
</qual:transition>
<qual:transition qual:id="tr_S_18">
<notes>
<body xmlns="http://www.w3.org/1999/xhtml">
<p>SNAI1, NICD, and CTNNB1 all activate TWIST1.</p></body>
</notes>
<qual:listOfInputs>
<qual:input qual:id="tr_S_18_in_S_10" qual:qualitativeSpecies="S_10" qual:sign="positive" qual:thresholdLevel="1" qual:transitionEffect="none">
<notes>
<body xmlns="http://www.w3.org/1999/xhtml">
<p>CTNNB1 activates Twist1 transcription.</p></body>
</notes>
</qual:input>
<qual:input qual:id="tr_S_18_in_S_12" qual:qualitativeSpecies="S_12" qual:sign="positive" qual:thresholdLevel="1" qual:transitionEffect="none">
<notes>
<body xmlns="http://www.w3.org/1999/xhtml">
<p>SNAI1 is needed for up-regulation of Twist1 mRNA.</p></body>
</notes>
</qual:input>
<qual:input qual:id="tr_S_18_in_S_28" qual:qualitativeSpecies="S_28" qual:sign="positive" qual:thresholdLevel="1" qual:transitionEffect="none">
<notes>
<body xmlns="http://www.w3.org/1999/xhtml">
<p>NICD activates Twist1 transcription.</p></body>
</notes>
</qual:input>
</qual:listOfInputs>
<qual:listOfOutputs>
<qual:output qual:qualitativeSpecies="S_18" qual:transitionEffect="assignmentLevel"/>
</qual:listOfOutputs>
<qual:listOfFunctionTerms>
<qual:defaultTerm qual:resultLevel="0">
</qual:defaultTerm>
<qual:functionTerm qual:resultLevel="1">
<math xmlns="http://www.w3.org/1998/Math/MathML">
<apply>
<or/>
<apply>
<or/>
<apply>
<eq/>
<ci> S_10 </ci>
<cn type="integer"> 1 </cn>
</apply>
<apply>
<eq/>
<ci> S_12 </ci>
<cn type="integer"> 1 </cn>
</apply>
</apply>
<apply>
<eq/>
<ci> S_28 </ci>
<cn type="integer"> 1 </cn>
</apply>
</apply>
</math>
</qual:functionTerm>
</qual:listOfFunctionTerms>
</qual:transition>
<qual:transition qual:id="tr_S_19">
<notes>
<body xmlns="http://www.w3.org/1999/xhtml">
<p>VIM activates Migration in conjunction with Invasion, EMT, ERK, and AKT2. AKT1, miR200, and p63 are all negative regulators of Migration which express dominance over VIM.</p></body>
</notes>
<qual:listOfInputs>
<qual:input qual:id="tr_S_19_in_S_26" qual:qualitativeSpecies="S_26" qual:sign="negative" qual:thresholdLevel="1" qual:transitionEffect="none">
<notes>
<body xmlns="http://www.w3.org/1999/xhtml">
<p>miR200 inhibits migration by downregulating fibronectin 1.</p></body>
</notes>
</qual:input>
<qual:input qual:id="tr_S_19_in_S_1" qual:qualitativeSpecies="S_1" qual:sign="positive" qual:thresholdLevel="1" qual:transitionEffect="none">
<notes>
<body xmlns="http://www.w3.org/1999/xhtml">
<p>ERK is necessary for the induction of migration by inhibiting AKT1.</p><p>ERK activates cofilin-mediated migration.</p></body>
</notes>
</qual:input>
<qual:input qual:id="tr_S_19_in_S_8" qual:qualitativeSpecies="S_8" qual:sign="positive" qual:thresholdLevel="1" qual:transitionEffect="none">
<notes>
<body xmlns="http://www.w3.org/1999/xhtml">
<p>Inhibition of AKT2 compromises migration.</p><p>In breast and ovarian cancer cells, AKT2 stimulates migration through thr upregulation of beta integrins.</p></body>
</notes>
</qual:input>
<qual:input qual:id="tr_S_19_in_S_2" qual:qualitativeSpecies="S_2" qual:sign="positive" qual:thresholdLevel="1" qual:transitionEffect="none">
<notes>
<body xmlns="http://www.w3.org/1999/xhtml">
<p>Overexpression of VIM increases cell motility and directional migration.</p></body>
</notes>
</qual:input>
<qual:input qual:id="tr_S_19_in_S_6" qual:qualitativeSpecies="S_6" qual:sign="negative" qual:thresholdLevel="1" qual:transitionEffect="none">
<notes>
<body xmlns="http://www.w3.org/1999/xhtml">
<p>AKT1 inhibits migration through degradation of NFAT.</p><p>AKT1 inhibits migration through phosphorylation of palladin.</p></body>
</notes>
</qual:input>
<qual:input qual:id="tr_S_19_in_S_7" qual:qualitativeSpecies="S_7" qual:sign="positive" qual:thresholdLevel="1" qual:transitionEffect="none">
<notes>
<body xmlns="http://www.w3.org/1999/xhtml">
<p>EMT promotes cell migration.</p></body>
</notes>
</qual:input>
<qual:input qual:id="tr_S_19_in_S_31" qual:qualitativeSpecies="S_31" qual:sign="positive" qual:thresholdLevel="1" qual:transitionEffect="none">
<notes>
<body xmlns="http://www.w3.org/1999/xhtml">
<p>In order for cells to migrate to other parts if the body, they must first be able to breach the basement membrane and extracellular matrix.</p></body>
</notes>
</qual:input>
<qual:input qual:id="tr_S_19_in_S_25" qual:qualitativeSpecies="S_25" qual:sign="negative" qual:thresholdLevel="1" qual:transitionEffect="none">
<notes>
<body xmlns="http://www.w3.org/1999/xhtml">
<p>Decrease in p63 levels leads to an increase in proteins involved in cell motility.</p></body>
</notes>
</qual:input>
</qual:listOfInputs>
<qual:listOfOutputs>
<qual:output qual:qualitativeSpecies="S_19" qual:transitionEffect="assignmentLevel"/>
</qual:listOfOutputs>
<qual:listOfFunctionTerms>
<qual:defaultTerm qual:resultLevel="0">
</qual:defaultTerm>
<qual:functionTerm qual:resultLevel="1">
<math xmlns="http://www.w3.org/1998/Math/MathML">
<apply>
<and/>
<apply>
<and/>
<apply>
<eq/>
<ci> S_2 </ci>
<cn type="integer"> 1 </cn>
</apply>
<apply>
<and/>
<apply>
<and/>
<apply>
<and/>
<apply>
<eq/>
<ci> S_1 </ci>
<cn type="integer"> 1 </cn>
</apply>
<apply>
<eq/>
<ci> S_8 </ci>
<cn type="integer"> 1 </cn>
</apply>
</apply>
<apply>
<eq/>
<ci> S_7 </ci>
<cn type="integer"> 1 </cn>
</apply>
</apply>
<apply>
<eq/>
<ci> S_31 </ci>
<cn type="integer"> 1 </cn>
</apply>
</apply>
</apply>
<apply>
<not/>
<apply>
<or/>
<apply>
<or/>
<apply>
<eq/>
<ci> S_6 </ci>
<cn type="integer"> 1 </cn>
</apply>
<apply>
<eq/>
<ci> S_25 </ci>
<cn type="integer"> 1 </cn>
</apply>
</apply>
<apply>
<eq/>
<ci> S_26 </ci>
<cn type="integer"> 1 </cn>
</apply>
</apply>
</apply>
</apply>
</math>
</qual:functionTerm>
</qual:listOfFunctionTerms>
</qual:transition>
<qual:transition qual:id="tr_S_20">
<notes>
<body xmlns="http://www.w3.org/1999/xhtml">
<p>When SNAI1, ZEB1, and ZEB2 are inactive, AKT2 activates miR34 in the presence of either p53 or p73. AKT1 and p63 are both inhibitors of miR34 that express dominance over AKT2.</p></body>
</notes>
<qual:listOfInputs>
<qual:input qual:id="tr_S_20_in_S_12" qual:qualitativeSpecies="S_12" qual:sign="negative" qual:thresholdLevel="1" qual:transitionEffect="none">
<notes>
<body xmlns="http://www.w3.org/1999/xhtml">
<p>SNAI1 represses miR34 expression through binding to E-boxes in the miR-34 promoter.</p></body>
</notes>
</qual:input>
<qual:input qual:id="tr_S_20_in_S_5" qual:qualitativeSpecies="S_5" qual:sign="negative" qual:thresholdLevel="1" qual:transitionEffect="none">
<notes>
<body xmlns="http://www.w3.org/1999/xhtml">
<p>ZEB1 represses miR34 expression through binding to E-boxes in the miR-34 promoter.</p></body>
</notes>
</qual:input>
<qual:input qual:id="tr_S_20_in_S_8" qual:qualitativeSpecies="S_8" qual:sign="positive" qual:thresholdLevel="1" qual:transitionEffect="none">
<notes>
<body xmlns="http://www.w3.org/1999/xhtml">
<p>AKT2 induces microRNAs</p></body>
</notes>
</qual:input>
<qual:input qual:id="tr_S_20_in_S_6" qual:qualitativeSpecies="S_6" qual:sign="negative" qual:thresholdLevel="1" qual:transitionEffect="none">
<notes>
<body xmlns="http://www.w3.org/1999/xhtml">
<p>AKT1 inhibits microRNAs</p></body>
</notes>
</qual:input>
<qual:input qual:id="tr_S_20_in_S_25" qual:qualitativeSpecies="S_25" qual:sign="negative" qual:thresholdLevel="1" qual:transitionEffect="none">
<notes>
<body xmlns="http://www.w3.org/1999/xhtml">
<p>p63 inhibits miR34 activity by directly binding to p53-consensus sites in the miR34 regulatory regions.</p></body>
</notes>
</qual:input>
<qual:input qual:id="tr_S_20_in_S_27" qual:qualitativeSpecies="S_27" qual:sign="positive" qual:thresholdLevel="1" qual:transitionEffect="none">
<notes>
<body xmlns="http://www.w3.org/1999/xhtml">
<p>p53 transcriptionally activates miR34.</p></body>
</notes>
</qual:input>
<qual:input qual:id="tr_S_20_in_S_15" qual:qualitativeSpecies="S_15" qual:sign="negative" qual:thresholdLevel="1" qual:transitionEffect="none"/>
<qual:input qual:id="tr_S_20_in_S_13" qual:qualitativeSpecies="S_13" qual:sign="positive" qual:thresholdLevel="1" qual:transitionEffect="none">
<notes>
<body xmlns="http://www.w3.org/1999/xhtml">
<p>p73 induces transcription of miR34.</p></body>
</notes>
</qual:input>
</qual:listOfInputs>
<qual:listOfOutputs>
<qual:output qual:qualitativeSpecies="S_20" qual:transitionEffect="assignmentLevel"/>
</qual:listOfOutputs>
<qual:listOfFunctionTerms>
<qual:defaultTerm qual:resultLevel="0">
</qual:defaultTerm>
<qual:functionTerm qual:resultLevel="1">
<math xmlns="http://www.w3.org/1998/Math/MathML">
<apply>
<and/>
<apply>
<and/>
<apply>
<and/>
<apply>
<eq/>
<ci> S_8 </ci>
<cn type="integer"> 1 </cn>
</apply>
<apply>
<and/>
<apply>
<and/>
<apply>
<not/>
<apply>
<eq/>
<ci> S_12 </ci>
<cn type="integer"> 1 </cn>
</apply>
</apply>
<apply>
<not/>
<apply>
<eq/>
<ci> S_5 </ci>
<cn type="integer"> 1 </cn>
</apply>
</apply>
</apply>
<apply>
<not/>
<apply>
<eq/>
<ci> S_15 </ci>
<cn type="integer"> 1 </cn>
</apply>
</apply>
</apply>
</apply>
<apply>
<or/>
<apply>
<eq/>
<ci> S_27 </ci>
<cn type="integer"> 1 </cn>
</apply>
<apply>
<eq/>
<ci> S_13 </ci>
<cn type="integer"> 1 </cn>
</apply>
</apply>
</apply>
<apply>
<not/>
<apply>
<or/>
<apply>
<eq/>
<ci> S_6 </ci>
<cn type="integer"> 1 </cn>
</apply>
<apply>
<eq/>
<ci> S_25 </ci>
<cn type="integer"> 1 </cn>
</apply>
</apply>
</apply>
</apply>
</math>
</qual:functionTerm>
</qual:listOfFunctionTerms>
</qual:transition>
<qual:transition qual:id="tr_S_21">
<notes>
<body xmlns="http://www.w3.org/1999/xhtml">
<p>ZEB2, p21, miR34, miR200, and miR203 all activate CellCycleArrest. AKT1 is an inhibitor of CellCycleArrest that is dominant over ZEB2, p21, miR34, miR200, and miR203.</p></body>
</notes>
<qual:listOfInputs>
<qual:input qual:id="tr_S_21_in_S_26" qual:qualitativeSpecies="S_26" qual:sign="positive" qual:thresholdLevel="1" qual:transitionEffect="none">
<notes>
<body xmlns="http://www.w3.org/1999/xhtml">
<p>miR200 induces cell cycle arrest by inhibiting CCNE2 (cyclin E).</p></body>
</notes>
</qual:input>
<qual:input qual:id="tr_S_21_in_S_32" qual:qualitativeSpecies="S_32" qual:sign="positive" qual:thresholdLevel="1" qual:transitionEffect="none">
<notes>
<body xmlns="http://www.w3.org/1999/xhtml">
<p>miR203 inhibits cell cycle progression by downregulating CDK6.</p></body>
</notes>
</qual:input>
<qual:input qual:id="tr_S_21_in_S_20" qual:qualitativeSpecies="S_20" qual:sign="positive" qual:thresholdLevel="1" qual:transitionEffect="none">
<notes>
<body xmlns="http://www.w3.org/1999/xhtml">
<p>miR34 prevents cell cycle progression by inhibiting Cyclin D1 activity.</p></body>
</notes>
</qual:input>
<qual:input qual:id="tr_S_21_in_S_4" qual:qualitativeSpecies="S_4" qual:sign="positive" qual:thresholdLevel="1" qual:transitionEffect="none">
<notes>
<body xmlns="http://www.w3.org/1999/xhtml">
<p>p21 is a cyclin-dependent kinase inhibitor that induces cell cycle arrest in response to a range of stimuli.</p></body>
</notes>
</qual:input>
<qual:input qual:id="tr_S_21_in_S_6" qual:qualitativeSpecies="S_6" qual:sign="negative" qual:thresholdLevel="1" qual:transitionEffect="none">
<notes>
<body xmlns="http://www.w3.org/1999/xhtml">
<p>AKT1 is required for cell proliferation.</p></body>
</notes>
</qual:input>
<qual:input qual:id="tr_S_21_in_S_15" qual:qualitativeSpecies="S_15" qual:sign="positive" qual:thresholdLevel="1" qual:transitionEffect="none">
<notes>
<body xmlns="http://www.w3.org/1999/xhtml">
<p>ZEB2 induces cell cycle arrest by inhibiting Cyclin D.</p></body>
</notes>
</qual:input>
</qual:listOfInputs>
<qual:listOfOutputs>
<qual:output qual:qualitativeSpecies="S_21" qual:transitionEffect="assignmentLevel"/>
</qual:listOfOutputs>
<qual:listOfFunctionTerms>
<qual:defaultTerm qual:resultLevel="0">
</qual:defaultTerm>
<qual:functionTerm qual:resultLevel="1">
<math xmlns="http://www.w3.org/1998/Math/MathML">
<apply>
<or/>
<apply>
<or/>
<apply>
<or/>
<apply>
<or/>
<apply>
<and/>
<apply>
<eq/>
<ci> S_20 </ci>
<cn type="integer"> 1 </cn>
</apply>
<apply>
<not/>
<apply>
<eq/>
<ci> S_6 </ci>
<cn type="integer"> 1 </cn>
</apply>
</apply>
</apply>
<apply>
<and/>
<apply>
<eq/>
<ci> S_32 </ci>
<cn type="integer"> 1 </cn>
</apply>
<apply>
<not/>
<apply>
<eq/>
<ci> S_6 </ci>
<cn type="integer"> 1 </cn>
</apply>
</apply>
</apply>
</apply>
<apply>
<and/>
<apply>
<eq/>
<ci> S_4 </ci>
<cn type="integer"> 1 </cn>
</apply>
<apply>
<not/>
<apply>
<eq/>
<ci> S_6 </ci>
<cn type="integer"> 1 </cn>
</apply>
</apply>
</apply>
</apply>
<apply>
<and/>
<apply>
<eq/>
<ci> S_26 </ci>
<cn type="integer"> 1 </cn>
</apply>
<apply>
<not/>
<apply>
<eq/>
<ci> S_6 </ci>
<cn type="integer"> 1 </cn>
</apply>
</apply>
</apply>
</apply>
<apply>
<and/>
<apply>
<eq/>
<ci> S_15 </ci>
<cn type="integer"> 1 </cn>
</apply>
<apply>
<not/>
<apply>
<eq/>
<ci> S_6 </ci>
<cn type="integer"> 1 </cn>
</apply>
</apply>
</apply>
</apply>
</math>
</qual:functionTerm>
</qual:listOfFunctionTerms>
</qual:transition>
<qual:transition qual:id="tr_S_23">
<notes>
<body xmlns="http://www.w3.org/1999/xhtml">
<p>DKK1 is activated by CTNNB1 and NICD.</p></body>
</notes>
<qual:listOfInputs>
<qual:input qual:id="tr_S_23_in_S_10" qual:qualitativeSpecies="S_10" qual:sign="positive" qual:thresholdLevel="1" qual:transitionEffect="none">
<notes>
<body xmlns="http://www.w3.org/1999/xhtml">
<p>DKK1 is a downstream target of CTNNB1.</p></body>
</notes>
</qual:input>
<qual:input qual:id="tr_S_23_in_S_28" qual:qualitativeSpecies="S_28" qual:sign="positive" qual:thresholdLevel="1" qual:transitionEffect="none">
<notes>
<body xmlns="http://www.w3.org/1999/xhtml">
<p>Two Notch-response elements were identified in the DKK1 promoter, indicating that DKK1 is a target of Notch signaling.</p></body>
</notes>
</qual:input>
</qual:listOfInputs>
<qual:listOfOutputs>
<qual:output qual:qualitativeSpecies="S_23" qual:transitionEffect="assignmentLevel"/>
</qual:listOfOutputs>
<qual:listOfFunctionTerms>
<qual:defaultTerm qual:resultLevel="0">
</qual:defaultTerm>
<qual:functionTerm qual:resultLevel="1">
<math xmlns="http://www.w3.org/1998/Math/MathML">
<apply>
<or/>
<apply>
<eq/>
<ci> S_28 </ci>
<cn type="integer"> 1 </cn>
</apply>
<apply>
<eq/>
<ci> S_10 </ci>
<cn type="integer"> 1 </cn>
</apply>
</apply>
</math>
</qual:functionTerm>
</qual:listOfFunctionTerms>
</qual:transition>
<qual:transition qual:id="tr_S_25">
<notes>
<body xmlns="http://www.w3.org/1999/xhtml">
<p>p63 is activated by DNAdamage. AKT1, AKT2, miR203, NICD, and p53 are all inhibitors of p63 which express dominance over DNAdamage.</p></body>
</notes>
<qual:listOfInputs>
<qual:input qual:id="tr_S_25_in_S_32" qual:qualitativeSpecies="S_32" qual:sign="negative" qual:thresholdLevel="1" qual:transitionEffect="none">
<notes>
<body xmlns="http://www.w3.org/1999/xhtml">
<p>miR203 targets human and mouse p63 3'-UTRs.</p></body>
</notes>
</qual:input>
<qual:input qual:id="tr_S_25_in_S_28" qual:qualitativeSpecies="S_28" qual:sign="negative" qual:thresholdLevel="1" qual:transitionEffect="none">
<notes>
<body xmlns="http://www.w3.org/1999/xhtml">
<p>Notch represses p63 expression.</p></body>
</notes>
</qual:input>
<qual:input qual:id="tr_S_25_in_S_8" qual:qualitativeSpecies="S_8" qual:sign="negative" qual:thresholdLevel="1" qual:transitionEffect="none">
<notes>
<body xmlns="http://www.w3.org/1999/xhtml">
<p>AKT2 inhibits p63 through MDM2-mediated degradation.</p></body>
</notes>
</qual:input>
<qual:input qual:id="tr_S_25_in_S_22" qual:qualitativeSpecies="S_22" qual:sign="positive" qual:thresholdLevel="1" qual:transitionEffect="none">
<notes>
<body xmlns="http://www.w3.org/1999/xhtml">
<p>p63 is important in regulating DNA repair systems after the introduction of DNA damage.</p></body>
</notes>
</qual:input>
<qual:input qual:id="tr_S_25_in_S_6" qual:qualitativeSpecies="S_6" qual:sign="negative" qual:thresholdLevel="1" qual:transitionEffect="none">
<notes>
<body xmlns="http://www.w3.org/1999/xhtml">
<p>AKT1 inhibits p63 through MDM2-mediated degradation.</p></body>
</notes>
</qual:input>
<qual:input qual:id="tr_S_25_in_S_27" qual:qualitativeSpecies="S_27" qual:sign="negative" qual:thresholdLevel="1" qual:transitionEffect="none">
<notes>
<body xmlns="http://www.w3.org/1999/xhtml">
<p>p53 initiates cell cycle arrest by inducing the synthesis of p21.</p></body>
</notes>
</qual:input>
</qual:listOfInputs>
<qual:listOfOutputs>
<qual:output qual:qualitativeSpecies="S_25" qual:transitionEffect="assignmentLevel"/>
</qual:listOfOutputs>
<qual:listOfFunctionTerms>
<qual:defaultTerm qual:resultLevel="0">
</qual:defaultTerm>
<qual:functionTerm qual:resultLevel="1">
<math xmlns="http://www.w3.org/1998/Math/MathML">
<apply>
<and/>
<apply>
<eq/>
<ci> S_22 </ci>
<cn type="integer"> 1 </cn>
</apply>
<apply>
<not/>
<apply>
<or/>
<apply>
<or/>
<apply>
<or/>
<apply>
<or/>
<apply>
<eq/>
<ci> S_28 </ci>
<cn type="integer"> 1 </cn>
</apply>
<apply>
<eq/>
<ci> S_27 </ci>
<cn type="integer"> 1 </cn>
</apply>
</apply>
<apply>
<eq/>
<ci> S_6 </ci>
<cn type="integer"> 1 </cn>
</apply>
</apply>
<apply>
<eq/>
<ci> S_8 </ci>
<cn type="integer"> 1 </cn>
</apply>
</apply>
<apply>
<eq/>
<ci> S_32 </ci>
<cn type="integer"> 1 </cn>
</apply>
</apply>
</apply>
</apply>
</math>
</qual:functionTerm>
</qual:listOfFunctionTerms>
</qual:transition>
<qual:transition qual:id="tr_S_26">
<notes>
<body xmlns="http://www.w3.org/1999/xhtml">
<p>p53, p63, and p73 all upregulate miR200. AKT2, SNAI1, SNAI2, ZEB1, and ZEB2 all inhibit miR200 and express dominance over p53, p63, and p73.</p></body>
</notes>
<qual:listOfInputs>
<qual:input qual:id="tr_S_26_in_S_5" qual:qualitativeSpecies="S_5" qual:sign="negative" qual:thresholdLevel="1" qual:transitionEffect="none">
<notes>
<body xmlns="http://www.w3.org/1999/xhtml">
<p>ZEB1 is involved in a double-negative feedback loop with miR200.</p></body>
</notes>
</qual:input>
<qual:input qual:id="tr_S_26_in_S_12" qual:qualitativeSpecies="S_12" qual:sign="negative" qual:thresholdLevel="1" qual:transitionEffect="none">
<notes>
<body xmlns="http://www.w3.org/1999/xhtml">
<p>miR200 promoter activity significantly decreased upon 12 h of SNAI1 induction.</p></body>
</notes>
</qual:input>
<qual:input qual:id="tr_S_26_in_S_8" qual:qualitativeSpecies="S_8" qual:sign="negative" qual:thresholdLevel="1" qual:transitionEffect="none">
<notes>
<body xmlns="http://www.w3.org/1999/xhtml">
<p>Cell expressing AKT2 observed a decrease in miR200 abundance.</p></body>
</notes>
</qual:input>
<qual:input qual:id="tr_S_26_in_S_17" qual:qualitativeSpecies="S_17" qual:sign="negative" qual:thresholdLevel="1" qual:transitionEffect="none">
<notes>
<body xmlns="http://www.w3.org/1999/xhtml">
<p>SNAI2 inhibits miR200 expression.</p></body>
</notes>
</qual:input>
<qual:input qual:id="tr_S_26_in_S_25" qual:qualitativeSpecies="S_25" qual:sign="positive" qual:thresholdLevel="1" qual:transitionEffect="none">
<notes>
<body xmlns="http://www.w3.org/1999/xhtml">
<p>p63 activates transcription of the miR200 family.</p></body>
</notes>
</qual:input>
<qual:input qual:id="tr_S_26_in_S_27" qual:qualitativeSpecies="S_27" qual:sign="positive" qual:thresholdLevel="1" qual:transitionEffect="none">
<notes>
<body xmlns="http://www.w3.org/1999/xhtml">
<p>p53 activates transcription of miR200c.</p></body>
</notes>
</qual:input>
<qual:input qual:id="tr_S_26_in_S_15" qual:qualitativeSpecies="S_15" qual:sign="negative" qual:thresholdLevel="1" qual:transitionEffect="none">
<notes>
<body xmlns="http://www.w3.org/1999/xhtml">
<p>ZEB2 is involved in a double-negative feedback loop with miR200.</p></body>
</notes>
</qual:input>
<qual:input qual:id="tr_S_26_in_S_13" qual:qualitativeSpecies="S_13" qual:sign="positive" qual:thresholdLevel="1" qual:transitionEffect="none">
<notes>
<body xmlns="http://www.w3.org/1999/xhtml">
<p>p73 activates transcription of the miR200 family.</p></body>
</notes>
</qual:input>
</qual:listOfInputs>
<qual:listOfOutputs>
<qual:output qual:qualitativeSpecies="S_26" qual:transitionEffect="assignmentLevel"/>
</qual:listOfOutputs>
<qual:listOfFunctionTerms>
<qual:defaultTerm qual:resultLevel="0">
</qual:defaultTerm>
<qual:functionTerm qual:resultLevel="1">
<math xmlns="http://www.w3.org/1998/Math/MathML">
<apply>
<or/>
<apply>
<or/>
<apply>
<and/>
<apply>
<eq/>
<ci> S_27 </ci>
<cn type="integer"> 1 </cn>
</apply>
<apply>
<not/>
<apply>
<or/>
<apply>
<or/>
<apply>
<or/>
<apply>
<or/>
<apply>
<eq/>
<ci> S_5 </ci>
<cn type="integer"> 1 </cn>
</apply>
<apply>
<eq/>
<ci> S_12 </ci>
<cn type="integer"> 1 </cn>
</apply>
</apply>
<apply>
<eq/>
<ci> S_17 </ci>
<cn type="integer"> 1 </cn>
</apply>
</apply>
<apply>
<eq/>
<ci> S_8 </ci>
<cn type="integer"> 1 </cn>
</apply>
</apply>
<apply>
<eq/>
<ci> S_15 </ci>
<cn type="integer"> 1 </cn>
</apply>
</apply>
</apply>
</apply>
<apply>
<and/>
<apply>
<eq/>
<ci> S_13 </ci>
<cn type="integer"> 1 </cn>
</apply>
<apply>
<not/>
<apply>
<or/>
<apply>
<or/>
<apply>
<or/>
<apply>
<or/>
<apply>
<eq/>
<ci> S_5 </ci>
<cn type="integer"> 1 </cn>
</apply>
<apply>
<eq/>
<ci> S_12 </ci>
<cn type="integer"> 1 </cn>
</apply>
</apply>
<apply>
<eq/>
<ci> S_17 </ci>
<cn type="integer"> 1 </cn>
</apply>
</apply>
<apply>
<eq/>
<ci> S_8 </ci>
<cn type="integer"> 1 </cn>
</apply>
</apply>
<apply>
<eq/>
<ci> S_15 </ci>
<cn type="integer"> 1 </cn>
</apply>
</apply>
</apply>
</apply>
</apply>
<apply>
<and/>
<apply>
<eq/>
<ci> S_25 </ci>
<cn type="integer"> 1 </cn>
</apply>
<apply>
<not/>
<apply>
<or/>
<apply>
<or/>
<apply>
<or/>
<apply>
<or/>
<apply>
<eq/>
<ci> S_5 </ci>
<cn type="integer"> 1 </cn>
</apply>
<apply>
<eq/>
<ci> S_12 </ci>
<cn type="integer"> 1 </cn>
</apply>
</apply>
<apply>
<eq/>
<ci> S_17 </ci>
<cn type="integer"> 1 </cn>
</apply>
</apply>
<apply>
<eq/>
<ci> S_8 </ci>
<cn type="integer"> 1 </cn>
</apply>
</apply>
<apply>
<eq/>
<ci> S_15 </ci>
<cn type="integer"> 1 </cn>
</apply>
</apply>
</apply>
</apply>
</apply>
</math>
</qual:functionTerm>
</qual:listOfFunctionTerms>
</qual:transition>
<qual:transition qual:id="tr_S_27">
<notes>
<body xmlns="http://www.w3.org/1999/xhtml">
<p>CTNNB1, DNAdamage, miR34, and NICD all activate p53. SNAI2, p73, AKT1, and AKT2 are all negative regulators of p53 which express dominance over CTNNB1, DNAdamage, miR34, and NICD.</p></body>
</notes>
<qual:listOfInputs>
<qual:input qual:id="tr_S_27_in_S_10" qual:qualitativeSpecies="S_10" qual:sign="positive" qual:thresholdLevel="1" qual:transitionEffect="none">
<notes>
<body xmlns="http://www.w3.org/1999/xhtml">
<p>CTNNB1 upregulates p53 by inhibiting MDM2 through activation of p14ARF.</p></body>
</notes>
</qual:input>
<qual:input qual:id="tr_S_27_in_S_28" qual:qualitativeSpecies="S_28" qual:sign="positive" qual:thresholdLevel="1" qual:transitionEffect="none">
<notes>
<body xmlns="http://www.w3.org/1999/xhtml">
<p>NICD activates myc. This in turn activates p14ARF, which inhibits MDM2-mediated degradation of p53.</p></body>
</notes>
</qual:input>
<qual:input qual:id="tr_S_27_in_S_8" qual:qualitativeSpecies="S_8" qual:sign="negative" qual:thresholdLevel="1" qual:transitionEffect="none">
<notes>
<body xmlns="http://www.w3.org/1999/xhtml">
<p>AKT1 inhibits p53 via MDM2-mediated degradation.</p></body>
</notes>
</qual:input>
<qual:input qual:id="tr_S_27_in_S_20" qual:qualitativeSpecies="S_20" qual:sign="positive" qual:thresholdLevel="1" qual:transitionEffect="none">
<notes>
<body xmlns="http://www.w3.org/1999/xhtml">
<p>MiR34a upregulates p53 expression by inhibiting sirt1, a negative regulator of p53.</p></body>
</notes>
</qual:input>
<qual:input qual:id="tr_S_27_in_S_6" qual:qualitativeSpecies="S_6" qual:sign="negative" qual:thresholdLevel="1" qual:transitionEffect="none">
<notes>
<body xmlns="http://www.w3.org/1999/xhtml">
<p>AKT1 inhibits p53 via MDM2-mediated degradation.</p></body>
</notes>
</qual:input>
<qual:input qual:id="tr_S_27_in_S_22" qual:qualitativeSpecies="S_22" qual:sign="positive" qual:thresholdLevel="1" qual:transitionEffect="none">
<notes>
<body xmlns="http://www.w3.org/1999/xhtml">
<p>p53 is activated in response to DNA damage.</p></body>
</notes>
</qual:input>
<qual:input qual:id="tr_S_27_in_S_17" qual:qualitativeSpecies="S_17" qual:sign="negative" qual:thresholdLevel="1" qual:transitionEffect="none">
<notes>
<body xmlns="http://www.w3.org/1999/xhtml">
<p>SNAI2 inhibits p53 transcription.</p></body>
</notes>
</qual:input>
<qual:input qual:id="tr_S_27_in_S_13" qual:qualitativeSpecies="S_13" qual:sign="negative" qual:thresholdLevel="1" qual:transitionEffect="none">
<notes>
<body xmlns="http://www.w3.org/1999/xhtml">
<p>The truncated form of p73 is able to repress p53 activity. p73 can bind to and activate MDM2, leading to the degradation of p53.</p></body>
</notes>
</qual:input>
</qual:listOfInputs>
<qual:listOfOutputs>
<qual:output qual:qualitativeSpecies="S_27" qual:transitionEffect="assignmentLevel"/>
</qual:listOfOutputs>
<qual:listOfFunctionTerms>
<qual:defaultTerm qual:resultLevel="0">
</qual:defaultTerm>
<qual:functionTerm qual:resultLevel="1">
<math xmlns="http://www.w3.org/1998/Math/MathML">
<apply>
<or/>
<apply>
<or/>
<apply>
<or/>
<apply>
<and/>
<apply>
<eq/>
<ci> S_22 </ci>
<cn type="integer"> 1 </cn>
</apply>
<apply>
<not/>
<apply>
<or/>
<apply>
<or/>
<apply>
<or/>
<apply>
<eq/>
<ci> S_17 </ci>
<cn type="integer"> 1 </cn>
</apply>
<apply>
<eq/>
<ci> S_6 </ci>
<cn type="integer"> 1 </cn>
</apply>
</apply>
<apply>
<eq/>
<ci> S_8 </ci>
<cn type="integer"> 1 </cn>
</apply>
</apply>
<apply>
<eq/>
<ci> S_13 </ci>
<cn type="integer"> 1 </cn>
</apply>
</apply>
</apply>
</apply>
<apply>
<and/>
<apply>
<eq/>
<ci> S_10 </ci>
<cn type="integer"> 1 </cn>
</apply>
<apply>
<not/>
<apply>
<or/>
<apply>
<or/>
<apply>
<or/>
<apply>
<eq/>
<ci> S_17 </ci>
<cn type="integer"> 1 </cn>
</apply>
<apply>
<eq/>
<ci> S_6 </ci>
<cn type="integer"> 1 </cn>
</apply>
</apply>
<apply>
<eq/>
<ci> S_8 </ci>
<cn type="integer"> 1 </cn>
</apply>
</apply>
<apply>
<eq/>
<ci> S_13 </ci>
<cn type="integer"> 1 </cn>
</apply>
</apply>
</apply>
</apply>
</apply>
<apply>
<and/>
<apply>
<eq/>
<ci> S_20 </ci>
<cn type="integer"> 1 </cn>
</apply>
<apply>
<not/>
<apply>
<or/>
<apply>
<or/>
<apply>
<or/>
<apply>
<eq/>
<ci> S_17 </ci>
<cn type="integer"> 1 </cn>
</apply>
<apply>
<eq/>
<ci> S_6 </ci>
<cn type="integer"> 1 </cn>
</apply>
</apply>
<apply>
<eq/>
<ci> S_8 </ci>
<cn type="integer"> 1 </cn>
</apply>
</apply>
<apply>
<eq/>
<ci> S_13 </ci>
<cn type="integer"> 1 </cn>
</apply>
</apply>
</apply>
</apply>
</apply>
<apply>
<and/>
<apply>
<eq/>
<ci> S_28 </ci>
<cn type="integer"> 1 </cn>
</apply>
<apply>
<not/>
<apply>
<or/>
<apply>
<or/>
<apply>
<or/>
<apply>
<eq/>
<ci> S_17 </ci>
<cn type="integer"> 1 </cn>
</apply>
<apply>
<eq/>
<ci> S_6 </ci>
<cn type="integer"> 1 </cn>
</apply>
</apply>
<apply>
<eq/>
<ci> S_8 </ci>
<cn type="integer"> 1 </cn>
</apply>
</apply>
<apply>
<eq/>
<ci> S_13 </ci>
<cn type="integer"> 1 </cn>
</apply>
</apply>
</apply>
</apply>
</apply>
</math>
</qual:functionTerm>
</qual:listOfFunctionTerms>
</qual:transition>
<qual:transition qual:id="tr_S_28">
<notes>
<body xmlns="http://www.w3.org/1999/xhtml">
<p>ECM activates NICD. miR34, miR200, p53, p63, and p73 all express dominance over ECM and inhibit NICD.</p></body>
</notes>
<qual:listOfInputs>
<qual:input qual:id="tr_S_28_in_S_26" qual:qualitativeSpecies="S_26" qual:sign="negative" qual:thresholdLevel="1" qual:transitionEffect="none">
<notes>
<body xmlns="http://www.w3.org/1999/xhtml">
<p>miR200 targets Notch pathway components, such as Jagged1.</p></body>
</notes>
</qual:input>
<qual:input qual:id="tr_S_28_in_S_20" qual:qualitativeSpecies="S_20" qual:sign="negative" qual:thresholdLevel="1" qual:transitionEffect="none">
<notes>
<body xmlns="http://www.w3.org/1999/xhtml">
<p>miR34 inhibits Notch1, which in turn inhibits NICD. (Observed in cervical carcinoma and chroiocarcinoma cells.)</p></body>
</notes>
</qual:input>
<qual:input qual:id="tr_S_28_in_S_25" qual:qualitativeSpecies="S_25" qual:sign="negative" qual:thresholdLevel="1" qual:transitionEffect="none">
<notes>
<body xmlns="http://www.w3.org/1999/xhtml">
<p>p63 activates Jag. Cis-interaction between Jag ligands inhibits Notch signalling within the same cell.</p></body>
</notes>
</qual:input>
<qual:input qual:id="tr_S_28_in_S_27" qual:qualitativeSpecies="S_27" qual:sign="negative" qual:thresholdLevel="1" qual:transitionEffect="none">
<notes>
<body xmlns="http://www.w3.org/1999/xhtml">
<p>p53 inhibits PSEN, which activates NICD.</p></body>
</notes>
</qual:input>
<qual:input qual:id="tr_S_28_in_S_13" qual:qualitativeSpecies="S_13" qual:sign="negative" qual:thresholdLevel="1" qual:transitionEffect="none">
<notes>
<body xmlns="http://www.w3.org/1999/xhtml">
<p>p63 activates Jag. Cis-interaction between Jag ligands inhibits Notch signalling within the same cell.</p></body>
</notes>
</qual:input>
<qual:input qual:id="tr_S_28_in_S_24" qual:qualitativeSpecies="S_24" qual:sign="positive" qual:thresholdLevel="1" qual:transitionEffect="none">
<notes>
<body xmlns="http://www.w3.org/1999/xhtml">
<p>ECM can upregulate NICD through laminin 411-mediated activation of Notch signaling.</p></body>
</notes>
</qual:input>
</qual:listOfInputs>
<qual:listOfOutputs>
<qual:output qual:qualitativeSpecies="S_28" qual:transitionEffect="assignmentLevel"/>
</qual:listOfOutputs>
<qual:listOfFunctionTerms>
<qual:defaultTerm qual:resultLevel="0">
</qual:defaultTerm>
<qual:functionTerm qual:resultLevel="1">
<math xmlns="http://www.w3.org/1998/Math/MathML">
<apply>
<and/>
<apply>
<eq/>
<ci> S_24 </ci>
<cn type="integer"> 1 </cn>
</apply>
<apply>
<not/>
<apply>
<or/>
<apply>
<or/>
<apply>
<or/>
<apply>
<or/>
<apply>
<eq/>
<ci> S_27 </ci>
<cn type="integer"> 1 </cn>
</apply>
<apply>
<eq/>
<ci> S_26 </ci>
<cn type="integer"> 1 </cn>
</apply>
</apply>
<apply>
<eq/>
<ci> S_25 </ci>
<cn type="integer"> 1 </cn>
</apply>
</apply>
<apply>
<eq/>
<ci> S_20 </ci>
<cn type="integer"> 1 </cn>
</apply>
</apply>
<apply>
<eq/>
<ci> S_13 </ci>
<cn type="integer"> 1 </cn>
</apply>
</apply>
</apply>
</apply>
</math>
</qual:functionTerm>
</qual:listOfFunctionTerms>
</qual:transition>
<qual:transition qual:id="tr_S_29">
<notes>
<body xmlns="http://www.w3.org/1999/xhtml">
<p>ECM and NICD are positive regulators of TGFbeta. CTNNB1 downregulates TGFbeta and is dominant to ECM and NICD.</p></body>
</notes>
<qual:listOfInputs>
<qual:input qual:id="tr_S_29_in_S_10" qual:qualitativeSpecies="S_10" qual:sign="negative" qual:thresholdLevel="1" qual:transitionEffect="none">
<notes>
<body xmlns="http://www.w3.org/1999/xhtml">
<p>CTNNB1 activates Bambi, which inhibit TGFbeta.</p></body>
</notes>
</qual:input>
<qual:input qual:id="tr_S_29_in_S_28" qual:qualitativeSpecies="S_28" qual:sign="positive" qual:thresholdLevel="1" qual:transitionEffect="none">
<notes>
<body xmlns="http://www.w3.org/1999/xhtml">
<p>Notch activates Nodal, which activates TGFbeta.</p></body>
</notes>
</qual:input>
<qual:input qual:id="tr_S_29_in_S_24" qual:qualitativeSpecies="S_24" qual:sign="positive" qual:thresholdLevel="1" qual:transitionEffect="none">
<notes>
<body xmlns="http://www.w3.org/1999/xhtml">
<p>The mechanical properties of the ECM determines TGFbeta activity and availability.</p></body>
</notes>
</qual:input>
</qual:listOfInputs>
<qual:listOfOutputs>
<qual:output qual:qualitativeSpecies="S_29" qual:transitionEffect="assignmentLevel"/>
</qual:listOfOutputs>
<qual:listOfFunctionTerms>
<qual:defaultTerm qual:resultLevel="0">
</qual:defaultTerm>
<qual:functionTerm qual:resultLevel="1">
<math xmlns="http://www.w3.org/1998/Math/MathML">
<apply>
<or/>
<apply>
<and/>
<apply>
<eq/>
<ci> S_28 </ci>
<cn type="integer"> 1 </cn>
</apply>
<apply>
<not/>
<apply>
<eq/>
<ci> S_10 </ci>
<cn type="integer"> 1 </cn>
</apply>
</apply>
</apply>
<apply>
<and/>
<apply>
<eq/>
<ci> S_24 </ci>
<cn type="integer"> 1 </cn>
</apply>
<apply>
<not/>
<apply>
<eq/>
<ci> S_10 </ci>
<cn type="integer"> 1 </cn>
</apply>
</apply>
</apply>
</apply>
</math>
</qual:functionTerm>
</qual:listOfFunctionTerms>
</qual:transition>
<qual:transition qual:id="tr_S_30">
<notes>
<body xmlns="http://www.w3.org/1999/xhtml">
<p>p53, p63, p73, miR200, and miR34 are all activators of Apoptosis. ERK, AKT1, and ZEB2 are inhibitors of Apoptosis which express dominance over p53, p63, p73, miR200, and miR34.</p></body>
</notes>
<qual:listOfInputs>
<qual:input qual:id="tr_S_30_in_S_26" qual:qualitativeSpecies="S_26" qual:sign="positive" qual:thresholdLevel="1" qual:transitionEffect="none">
<notes>
<body xmlns="http://www.w3.org/1999/xhtml">
<p>miR200 inhibits apoptosis be downregulating XIAP.</p></body>
</notes>
</qual:input>
<qual:input qual:id="tr_S_30_in_S_1" qual:qualitativeSpecies="S_1" qual:sign="negative" qual:thresholdLevel="1" qual:transitionEffect="none">
<notes>
<body xmlns="http://www.w3.org/1999/xhtml">
<p>ERK inhibits apoptosis by upegulating the expression of anti-apoptotic proteins such as Bcl2, Bcl-XL, and Mcl-2.</p></body>
</notes>
</qual:input>
<qual:input qual:id="tr_S_30_in_S_20" qual:qualitativeSpecies="S_20" qual:sign="positive" qual:thresholdLevel="1" qual:transitionEffect="none">
<notes>
<body xmlns="http://www.w3.org/1999/xhtml">
<p>miR34 activates apoptosis by inhibiting the anti-apoptotic gene BCL2.</p></body>
</notes>
</qual:input>
<qual:input qual:id="tr_S_30_in_S_6" qual:qualitativeSpecies="S_6" qual:sign="negative" qual:thresholdLevel="1" qual:transitionEffect="none">
<notes>
<body xmlns="http://www.w3.org/1999/xhtml">
<p>AKT1 suppresses anoikis (detachment-induced apoptosis).</p></body>
</notes>
</qual:input>
<qual:input qual:id="tr_S_30_in_S_25" qual:qualitativeSpecies="S_25" qual:sign="positive" qual:thresholdLevel="1" qual:transitionEffect="none">
<notes>
<body xmlns="http://www.w3.org/1999/xhtml">
<p>p63 suppresses anoikis (detachment-induced apoptosis) by downregulating integrin beta4.</p></body>
</notes>
</qual:input>
<qual:input qual:id="tr_S_30_in_S_27" qual:qualitativeSpecies="S_27" qual:sign="positive" qual:thresholdLevel="1" qual:transitionEffect="none">
<notes>
<body xmlns="http://www.w3.org/1999/xhtml">
<p>p53 induces anoikis (detachment-induced apoptosis).</p></body>
</notes>
</qual:input>
<qual:input qual:id="tr_S_30_in_S_15" qual:qualitativeSpecies="S_15" qual:sign="negative" qual:thresholdLevel="1" qual:transitionEffect="none">
<notes>
<body xmlns="http://www.w3.org/1999/xhtml">
<p>Downregulation of ZEB2 induces apoptosis through the activation of caspase-3.</p></body>
</notes>
</qual:input>
<qual:input qual:id="tr_S_30_in_S_13" qual:qualitativeSpecies="S_13" qual:sign="positive" qual:thresholdLevel="1" qual:transitionEffect="none">
<notes>
<body xmlns="http://www.w3.org/1999/xhtml">
<p>p73 is a p53 homolog and regulates some of the same gene targets as p53. Overexpression of p73 can also induce apoptosis, like p53.</p></body>
</notes>
</qual:input>
</qual:listOfInputs>
<qual:listOfOutputs>
<qual:output qual:qualitativeSpecies="S_30" qual:transitionEffect="assignmentLevel"/>
</qual:listOfOutputs>
<qual:listOfFunctionTerms>
<qual:defaultTerm qual:resultLevel="0">
</qual:defaultTerm>
<qual:functionTerm qual:resultLevel="1">
<math xmlns="http://www.w3.org/1998/Math/MathML">
<apply>
<or/>
<apply>
<or/>
<apply>
<or/>
<apply>
<or/>
<apply>
<and/>
<apply>
<eq/>
<ci> S_20 </ci>
<cn type="integer"> 1 </cn>
</apply>
<apply>
<not/>
<apply>
<or/>
<apply>
<or/>
<apply>
<eq/>
<ci> S_15 </ci>
<cn type="integer"> 1 </cn>
</apply>
<apply>
<eq/>
<ci> S_1 </ci>
<cn type="integer"> 1 </cn>
</apply>
</apply>
<apply>
<eq/>
<ci> S_6 </ci>
<cn type="integer"> 1 </cn>
</apply>
</apply>
</apply>
</apply>
<apply>
<and/>
<apply>
<eq/>
<ci> S_25 </ci>
<cn type="integer"> 1 </cn>
</apply>
<apply>
<not/>
<apply>
<or/>
<apply>
<or/>
<apply>
<eq/>
<ci> S_15 </ci>
<cn type="integer"> 1 </cn>
</apply>
<apply>
<eq/>
<ci> S_1 </ci>
<cn type="integer"> 1 </cn>
</apply>
</apply>
<apply>
<eq/>
<ci> S_6 </ci>
<cn type="integer"> 1 </cn>
</apply>
</apply>
</apply>
</apply>
</apply>
<apply>
<and/>
<apply>
<eq/>
<ci> S_27 </ci>
<cn type="integer"> 1 </cn>
</apply>
<apply>
<not/>
<apply>
<or/>
<apply>
<or/>
<apply>
<eq/>
<ci> S_15 </ci>
<cn type="integer"> 1 </cn>
</apply>
<apply>
<eq/>
<ci> S_1 </ci>
<cn type="integer"> 1 </cn>
</apply>
</apply>
<apply>
<eq/>
<ci> S_6 </ci>
<cn type="integer"> 1 </cn>
</apply>
</apply>
</apply>
</apply>
</apply>
<apply>
<and/>
<apply>
<eq/>
<ci> S_13 </ci>
<cn type="integer"> 1 </cn>
</apply>
<apply>
<not/>
<apply>
<or/>
<apply>
<or/>
<apply>
<eq/>
<ci> S_15 </ci>
<cn type="integer"> 1 </cn>
</apply>
<apply>
<eq/>
<ci> S_1 </ci>
<cn type="integer"> 1 </cn>
</apply>
</apply>
<apply>
<eq/>
<ci> S_6 </ci>
<cn type="integer"> 1 </cn>
</apply>
</apply>
</apply>
</apply>
</apply>
<apply>
<and/>
<apply>
<eq/>
<ci> S_26 </ci>
<cn type="integer"> 1 </cn>
</apply>
<apply>
<not/>
<apply>
<or/>
<apply>
<or/>
<apply>
<eq/>
<ci> S_15 </ci>
<cn type="integer"> 1 </cn>
</apply>
<apply>
<eq/>
<ci> S_1 </ci>
<cn type="integer"> 1 </cn>
</apply>
</apply>
<apply>
<eq/>
<ci> S_6 </ci>
<cn type="integer"> 1 </cn>
</apply>
</apply>
</apply>
</apply>
</apply>
</math>
</qual:functionTerm>
</qual:listOfFunctionTerms>
</qual:transition>
<qual:transition qual:id="tr_S_31">
<notes>
<body xmlns="http://www.w3.org/1999/xhtml">
<p>Invasion is actived by both CTNNB1 and SMAD in the presence of CDH2.</p></body>
</notes>
<qual:listOfInputs>
<qual:input qual:id="tr_S_31_in_S_10" qual:qualitativeSpecies="S_10" qual:sign="positive" qual:thresholdLevel="1" qual:transitionEffect="none">
<notes>
<body xmlns="http://www.w3.org/1999/xhtml">
<p>CTNNB1 induces invasion by activating transcription of MMPs.</p></body>
</notes>
</qual:input>
<qual:input qual:id="tr_S_31_in_S_3" qual:qualitativeSpecies="S_3" qual:sign="positive" qual:thresholdLevel="1" qual:transitionEffect="none"/>
<qual:input qual:id="tr_S_31_in_S_14" qual:qualitativeSpecies="S_14" qual:sign="positive" qual:thresholdLevel="1" qual:transitionEffect="none">
<notes>
<body xmlns="http://www.w3.org/1999/xhtml">
<p>N-cadherin promotes cancer invasion, potentially through the increase in production of MMP-9 production in cells expressing N-cadherin.</p></body>
</notes>
</qual:input>
</qual:listOfInputs>
<qual:listOfOutputs>
<qual:output qual:qualitativeSpecies="S_31" qual:transitionEffect="assignmentLevel"/>
</qual:listOfOutputs>
<qual:listOfFunctionTerms>
<qual:defaultTerm qual:resultLevel="0">
</qual:defaultTerm>
<qual:functionTerm qual:resultLevel="1">
<math xmlns="http://www.w3.org/1998/Math/MathML">
<apply>
<or/>
<apply>
<eq/>
<ci> S_10 </ci>
<cn type="integer"> 1 </cn>
</apply>
<apply>
<and/>
<apply>
<eq/>
<ci> S_3 </ci>
<cn type="integer"> 1 </cn>
</apply>
<apply>
<eq/>
<ci> S_14 </ci>
<cn type="integer"> 1 </cn>
</apply>
</apply>
</apply>
</math>
</qual:functionTerm>
</qual:listOfFunctionTerms>
</qual:transition>
<qual:transition qual:id="tr_S_32">
<notes>
<body xmlns="http://www.w3.org/1999/xhtml">
<p>miR203 is activated by p53. SNAI1, ZEB1, and ZEB2 all inhibit miR203 and express dominance over p53.</p></body>
</notes>
<qual:listOfInputs>
<qual:input qual:id="tr_S_32_in_S_12" qual:qualitativeSpecies="S_12" qual:sign="negative" qual:thresholdLevel="1" qual:transitionEffect="none">
<notes>
<body xmlns="http://www.w3.org/1999/xhtml">
<p>SNAI1 inhibits miR203 expression.</p></body>
</notes>
</qual:input>
<qual:input qual:id="tr_S_32_in_S_5" qual:qualitativeSpecies="S_5" qual:sign="negative" qual:thresholdLevel="1" qual:transitionEffect="none">
<notes>
<body xmlns="http://www.w3.org/1999/xhtml">
<p>ZEB1 inhibit miR203 promoter activity.</p></body>
</notes>
</qual:input>
<qual:input qual:id="tr_S_32_in_S_27" qual:qualitativeSpecies="S_27" qual:sign="positive" qual:thresholdLevel="1" qual:transitionEffect="none">
<notes>
<body xmlns="http://www.w3.org/1999/xhtml">
<p>p53 activates transcription of miR203 in keratinocytes.</p></body>
</notes>
</qual:input>
<qual:input qual:id="tr_S_32_in_S_15" qual:qualitativeSpecies="S_15" qual:sign="negative" qual:thresholdLevel="1" qual:transitionEffect="none">
<notes>
<body xmlns="http://www.w3.org/1999/xhtml">
<p>ZEB2 inhibit miR203 promoter activity.</p></body>
</notes>
</qual:input>
</qual:listOfInputs>
<qual:listOfOutputs>
<qual:output qual:qualitativeSpecies="S_32" qual:transitionEffect="assignmentLevel"/>
</qual:listOfOutputs>
<qual:listOfFunctionTerms>
<qual:defaultTerm qual:resultLevel="0">
</qual:defaultTerm>
<qual:functionTerm qual:resultLevel="1">
<math xmlns="http://www.w3.org/1998/Math/MathML">
<apply>
<and/>
<apply>
<eq/>
<ci> S_27 </ci>
<cn type="integer"> 1 </cn>
</apply>
<apply>
<not/>
<apply>
<or/>
<apply>
<or/>
<apply>
<eq/>
<ci> S_15 </ci>
<cn type="integer"> 1 </cn>
</apply>
<apply>
<eq/>
<ci> S_12 </ci>
<cn type="integer"> 1 </cn>
</apply>
</apply>
<apply>
<eq/>
<ci> S_5 </ci>
<cn type="integer"> 1 </cn>
</apply>
</apply>
</apply>
</apply>
</math>
</qual:functionTerm>
</qual:listOfFunctionTerms>
</qual:transition>
</qual:listOfTransitions>
<listOfCompartments>
<compartment constant="true" id="extracellular" name="extracellular"/>
<compartment constant="true" id="cytosol" name="cytosol"/>
</listOfCompartments>
</model>
</sbml>