To understand the design principles of the molecular interaction network associated with the irreversibility of cell apoptosis and the stability of cell surviving, we constructed a Boolean network integrating both the intrinsic and extrinsic pro-apoptotic pathways with pro-survival signal transduction pathways. We performed statistical analyses of the dependences of cell fate on initial states and on input signals. The analyses reproduced the well-known pro- and anti-apoptotic effects of key external signals and network components. We found that the external GF signal by itself did not change the apoptotic ratio from randomly chosen initial states when there is no external TNF signal, but can significantly offset apoptosis induced by the TNF signal. While a complete model produces the expected irreversibility of the apoptosis process, alternative models missing one or more of four selected inter-component connections indicate that the feedback loops directly involving the caspase 3 are essential for maintaining irreversibility of apoptosis. The feedback loops involving P53 showed compensating effects when those involving caspase 3 have been removed. The GF signal significantly increases the stability of the surviving states of the network. The apoptosis network seems to use different modules by design to control the irreversibility of the apoptosis process and the stability of the surviving states. Such a design may accommodate the needed plasticity for the network to adapt to different cellular environments: depending on the strength of external pro-surviving signals, apoptosis can be induced either easily or difficultly by pro-apoptotic signal of varying strengths, but proceed with invariable irreversibility. Helikar Tomas thelika@unmc.edu University of Nebraska - Lincoln 2014-02-01T14:41:22Z 2017-10-13T16:16:10Z 2015-11-15T19:54:34Z 2015-11-15T19:54:34Z

<div><span style="border: 0px; outline: 0px; line-height: 17px; vertical-align: baseline; margin: 0px; padding: 0px; background-color: rgb(255, 255, 255);"><span style="line-height: 17px;"><font face="Georgia" size="2">Phosphatidylinositol Triphosphate</font></span></span></div><div><font face="Georgia" size="2"><span style="border: 0px; outline: 0px; line-height: 17px; vertical-align: baseline; margin: 0px; padding: 0px; background-color: rgb(255, 255, 255);"><span style="line-height: 17px;">PubChem ID:</span></span><span style="line-height: 19px; background-color: rgb(255, 255, 255);"> </span><a name="cid2entrez" href="http://www.ncbi.nlm.nih.gov/sites/entrez?cmd=search&db=pccompound&term=53480352[uid]" style="border: 0px; outline: 0px; line-height: 19px; vertical-align: baseline; margin: 0px; padding: 0px; text-decoration: none; background-color: rgb(255, 255, 255);">53480352<br/></a><span style="border: 0px; outline: 0px; line-height: 17px; vertical-align: baseline; margin: 0px; padding: 0px; background-color: rgb(255, 255, 255);">Molecular Formula:</span><span style="line-height: 17px; background-color: rgb(255, 255, 255);"> C</span><sub style="border: 0px; outline: 0px; line-height: 0; margin: 0px; padding: 0px; background-color: rgb(255, 255, 255);">47</sub><span style="line-height: 17px; background-color: rgb(255, 255, 255);">H</span><sub style="border: 0px; outline: 0px; line-height: 0; margin: 0px; padding: 0px; background-color: rgb(255, 255, 255);">86</sub><span style="line-height: 17px; background-color: rgb(255, 255, 255);">O</span><sub style="border: 0px; outline: 0px; line-height: 0; margin: 0px; padding: 0px; background-color: rgb(255, 255, 255);">22</sub><span style="line-height: 17px; background-color: rgb(255, 255, 255);">P</span><sub style="border: 0px; outline: 0px; line-height: 0; margin: 0px; padding: 0px; background-color: rgb(255, 255, 255);">4</sub><span style="line-height: 17px; background-color: rgb(255, 255, 255);">   </span><span style="border: 0px; outline: 0px; line-height: 17px; vertical-align: baseline; margin: 0px; padding: 0px; background-color: rgb(255, 255, 255);">Molecular Weight:</span><span style="line-height: 17px; background-color: rgb(255, 255, 255);"> 1127.067588 </span></font></div><div style="font-weight: normal; font-size: 10pt; font-family: Arial, Verdana;"><span style="color: rgb(85, 85, 85); font-family: Arial, Verdana, sans-serif; font-size: 13px; line-height: 17px; background-color: rgb(255, 255, 255);"><br/></span></div>

2015-11-15T19:54:34Z

<font face="Georgia" size="2">Represents "growth family receptors" in the Apoptosis Network [1]. </font>

2015-11-15T19:54:34Z

<font face="Georgia" size="2"><span class="highlight" style="line-height: 19.999780654907227px; background-color: rgb(255, 255, 255);">Caspase</span><span style="line-height: 19.999780654907227px; background-color: rgb(255, 255, 255);"> </span><span class="highlight" style="line-height: 19.999780654907227px; background-color: rgb(255, 255, 255);">7</span><span style="line-height: 19.999780654907227px; background-color: rgb(255, 255, 255);">, apoptosis-related cysteine peptidase [</span><em style="line-height: 19.999780654907227px; background-color: rgb(255, 255, 255);">Homo sapiens</em><span style="line-height: 19.999780654907227px; background-color: rgb(255, 255, 255);">(human)]</span></font><div><font face="Georgia" size="2"><span style="line-height: 19.999780654907227px; background-color: rgb(255, 255, 255);">UniProt ID: </span><a href="http://www.uniprot.org/uniprot/P55210" style="text-decoration: none; background-color: rgb(255, 255, 255);">P55210</a></font></div><div><font face="Georgia" size="2"><span style="line-height: 19.999780654907227px; background-color: rgb(255, 255, 255);">Gene Name: </span><a href="http://www.ncbi.nlm.nih.gov/gene/840" ref="ordinalpos=1&ncbi_uid=840&link_uid=840" style="line-height: 19.999780654907227px; white-space: nowrap; background-color: rgb(255, 255, 255);">CASP7</a></font></div><div><font face="Georgia" size="2"><span style="line-height: 19.999780654907227px; background-color: rgb(255, 255, 255);">NCBI Gene ID: </span><span style="background-color: rgb(255, 255, 255); line-height: 17.999801635742188px;">840</span></font></div>

2015-11-15T19:54:34Z

<font face="Georgia" size="2"><span class="highlight" style="line-height: 18.88888931274414px; background-color: rgb(255, 255, 255);">Phosphatase</span><span style="line-height: 18.88888931274414px; background-color: rgb(255, 255, 255);"> and </span><span class="highlight" style="line-height: 18.88888931274414px; background-color: rgb(255, 255, 255);">tensin </span><span style="background-color: rgb(255, 255, 255); line-height: 18.88888931274414px;"></span><span class="highlight" style="line-height: 18.88888931274414px; background-color: rgb(255, 255, 255);">homolog</span><span style="line-height: 18.88888931274414px; background-color: rgb(255, 255, 255);"> [</span><em style="line-height: 18.88888931274414px; background-color: rgb(255, 255, 255);">Homo sapiens</em><span style="line-height: 18.88888931274414px; background-color: rgb(255, 255, 255);">(human)]</span></font><div><font face="Georgia" size="2"><span style="line-height: 18.88888931274414px; background-color: rgb(255, 255, 255);">UniProt ID: </span><a href="http://www.uniprot.org/uniprot/P60484" style="text-decoration: none; background-color: rgb(255, 255, 255);">P60484</a></font></div><div><font face="Georgia" size="2"><span style="line-height: 18.88888931274414px; background-color: rgb(255, 255, 255);">Gene Name:</span><a href="http://www.ncbi.nlm.nih.gov/gene/5728" ref="ordinalpos=1&ncbi_uid=5728&link_uid=5728" style="line-height: 18.88888931274414px; white-space: nowrap; background-color: rgb(255, 255, 255);">PTEN</a></font></div><div><font face="Georgia" size="2"><span style="line-height: 18.88888931274414px; background-color: rgb(255, 255, 255);">Gene ID: </span><span style="background-color: rgb(255, 255, 255); line-height: 17.77777862548828px;"> </span><span style="background-color: rgb(255, 255, 255); line-height: 17.77777862548828px;">5728</span></font></div>

2015-11-15T19:54:34Z

<font face="Georgia"><span style="font-size: 13.333333969116211px; line-height: 19.999780654907227px; background-color: rgb(255, 255, 255);">Tumor necrosis factor receptor superfamily, member 1B [</span><em style="font-size: 13.333333969116211px; line-height: 19.999780654907227px; background-color: rgb(255, 255, 255);">Homo sapiens</em><span style="font-size: 13.333333969116211px; line-height: 19.999780654907227px; background-color: rgb(255, 255, 255);"> (human)]</span></font><div><font face="Georgia"><span style="font-size: 13.333333969116211px; line-height: 19.999780654907227px; background-color: rgb(255, 255, 255);">UniProt ID: </span><a href="http://www.uniprot.org/uniprot/P20333" style="font-size: small; text-decoration: none; background-color: rgb(255, 255, 255);">P20333</a></font></div><div><font face="Georgia"><span style="font-size: 13.333333969116211px; line-height: 19.999780654907227px; background-color: rgb(255, 255, 255);">Gene Name: </span><a href="http://www.ncbi.nlm.nih.gov/gene/7133" ref="ordinalpos=3&ncbi_uid=7133&link_uid=7133" style="font-size: 13.333333969116211px; line-height: 19.999780654907227px; white-space: nowrap; background-color: rgb(255, 255, 255);">TNFRSF1B</a></font></div><div><font face="Georgia"><span style="font-size: 13.333333969116211px; line-height: 19.999780654907227px; background-color: rgb(255, 255, 255);">NCBI Gene ID: </span><span style="background-color: rgb(255, 255, 255); font-size: 12.222222328186035px; line-height: 17.999801635742188px;">7133</span></font></div>

2017-10-13T14:29:29Z

<font face="Georgia" size="2">Phosphatidylinositol-4,5-biphosphate</font><div><font face="Georgia" size="2"><span style="border: 0px; outline: 0px; line-height: 17.445960998535156px; vertical-align: baseline; margin: 0px; padding: 0px; background-color: rgb(255, 255, 255);">Molecular Formula:</span><span style="line-height: 17.445960998535156px; background-color: rgb(255, 255, 255);"> C</span><sub style="border: 0px; outline: 0px; line-height: 0; margin: 0px; padding: 0px; background-color: rgb(255, 255, 255);">9</sub><span style="line-height: 17.445960998535156px; background-color: rgb(255, 255, 255);">H</span><sub style="border: 0px; outline: 0px; line-height: 0; margin: 0px; padding: 0px; background-color: rgb(255, 255, 255);">21</sub><span style="line-height: 17.445960998535156px; background-color: rgb(255, 255, 255);">O</span><sub style="border: 0px; outline: 0px; line-height: 0; margin: 0px; padding: 0px; background-color: rgb(255, 255, 255);">17</sub><span style="line-height: 17.445960998535156px; background-color: rgb(255, 255, 255);">P</span><sub style="border: 0px; outline: 0px; line-height: 0; margin: 0px; padding: 0px; background-color: rgb(255, 255, 255);">3</sub><span style="line-height: 17.445960998535156px; background-color: rgb(255, 255, 255);">   </span><span style="border: 0px; outline: 0px; line-height: 17.445960998535156px; vertical-align: baseline; margin: 0px; padding: 0px; background-color: rgb(255, 255, 255);">Molecular Weight:</span><span style="line-height: 17.445960998535156px; background-color: rgb(255, 255, 255);"> 494.174126</span></font></div><div><font face="Georgia" size="2"><span style="line-height: 17.445960998535156px; background-color: rgb(255, 255, 255);">PubChem ID: </span><span style="background-color: rgb(255, 255, 255); line-height: 19.384401321411133px;"><a href="http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=125105">125105</a></span></font></div>

2015-11-15T19:54:34Z

<div><font face="Georgia" size="2"><span style="line-height: 19.999780654907227px; background-color: rgb(255, 255, 255);">Apoptotic peptidase activating factor 1 [</span><em style="line-height: 19.999780654907227px; background-color: rgb(255, 255, 255);">Homo sapiens</em><span style="line-height: 19.999780654907227px; background-color: rgb(255, 255, 255);">(human)]</span></font></div><font face="Georgia" size="2">Uniprot ID: <a href="http://www.uniprot.org/uniprot/O14727" style="text-decoration: none; background-color: rgb(255, 255, 255);">O14727</a></font><div><font face="Georgia" size="2">Gene Name: <a href="http://www.ncbi.nlm.nih.gov/gene/317" ref="ordinalpos=1&ncbi_uid=317&link_uid=317" style="line-height: 19.999780654907227px; white-space: nowrap; background-color: rgb(255, 255, 255);"><span class="highlight">APAF1</span></a></font></div><div><font face="Georgia" size="2">NCBI Gene ID: <span style="background-color: rgb(255, 255, 255); line-height: 17.999801635742188px;">317</span></font></div>

2015-11-15T19:54:34Z

<font face="Georgia"><span style="font-size: 13.333333969116211px; line-height: 19.999780654907227px; background-color: rgb(255, 255, 255);">TNF receptor-associated factor 2 [</span><em style="font-size: 13.333333969116211px; line-height: 19.999780654907227px; background-color: rgb(255, 255, 255);"><span class="highlight">Homo</span> sapiens</em><span style="font-size: 13.333333969116211px; line-height: 19.999780654907227px; background-color: rgb(255, 255, 255);">(human)]</span></font><div><font face="Georgia"><span style="font-size: 13.333333969116211px; line-height: 19.999780654907227px; background-color: rgb(255, 255, 255);">UniProt ID: </span><a href="http://www.uniprot.org/uniprot/Q12933" style="font-size: small; text-decoration: none; background-color: rgb(255, 255, 255);">Q12933</a></font></div><div><font face="Georgia"><span style="font-size: 13.333333969116211px; line-height: 19.999780654907227px; background-color: rgb(255, 255, 255);">Gene Name:</span><a href="http://www.ncbi.nlm.nih.gov/gene/7186" ref="ordinalpos=1&ncbi_uid=7186&link_uid=7186" style="font-size: 13.333333969116211px; line-height: 19.999780654907227px; white-space: nowrap; background-color: rgb(255, 255, 255);"><span class="highlight">TRAF2</span></a></font></div><div><font face="Georgia"><span style="font-size: 13.333333969116211px; line-height: 19.999780654907227px; background-color: rgb(255, 255, 255);">NCBI Gene ID: </span><span style="background-color: rgb(255, 255, 255); font-size: 12.222222328186035px; line-height: 17.999801635742188px;">7186</span></font></div>

2017-10-13T14:29:29Z

<font face="Georgia"><span style="font-size: 13.333333969116211px; line-height: 19.999780654907227px; background-color: rgb(255, 255, 255);">TNF receptor-associated factor 1 [</span><em style="font-size: 13.333333969116211px; line-height: 19.999780654907227px; background-color: rgb(255, 255, 255);"><span class="highlight">Homo</span> sapiens</em><span style="font-size: 13.333333969116211px; line-height: 19.999780654907227px; background-color: rgb(255, 255, 255);">(human)]</span></font><div><font face="Georgia"><span style="font-size: 13.333333969116211px; line-height: 19.999780654907227px; background-color: rgb(255, 255, 255);">UniProt ID:</span><a href="http://www.uniprot.org/uniprot/Q13077" style="font-size: small; text-decoration: none; background-color: rgb(255, 255, 255);">Q13077</a></font></div><div><font face="Georgia"><span style="font-size: 13.333333969116211px; line-height: 19.999780654907227px; background-color: rgb(255, 255, 255);">Gene Name:</span><a href="http://www.ncbi.nlm.nih.gov/gene/7185" ref="ordinalpos=1&ncbi_uid=7185&link_uid=7185" style="font-size: 13.333333969116211px; line-height: 19.999780654907227px; white-space: nowrap; background-color: rgb(255, 255, 255);"><span class="highlight">TRAF1</span></a></font></div><div><font face="Georgia"><span style="font-size: 13.333333969116211px; line-height: 19.999780654907227px; background-color: rgb(255, 255, 255);">NCBI Gene ID: </span><span style="background-color: rgb(255, 255, 255); font-size: 12.222222328186035px; line-height: 17.999801635742188px;">7185</span></font></div>

2017-07-19T10:59:00Z

<font face="Georgia"><span style="line-height: 19.999780654907227px; font-size: 13.333333969116211px; background-color: rgb(255, 255, 255);">Tumor necrosis factor receptor superfamily, member 1A [</span><em style="line-height: 19.999780654907227px; font-size: 13.333333969116211px; background-color: rgb(255, 255, 255);">Homo sapiens</em><span style="line-height: 19.999780654907227px; font-size: 13.333333969116211px; background-color: rgb(255, 255, 255);"> (human)]</span></font><div style="line-height: normal;"><font face="Georgia"><span style="font-size: 13.333333969116211px; line-height: 19.999780654907227px; background-color: rgb(255, 255, 255);">UniProt ID: </span><a href="http://www.uniprot.org/uniprot/P19438" style="font-size: small; text-decoration: none; background-color: rgb(255, 255, 255);">P19438</a></font></div><div style="line-height: normal;"><font face="Georgia"><span style="font-size: 13.333333969116211px; line-height: 19.999780654907227px; background-color: rgb(255, 255, 255);">Gene Name: </span><a href="http://www.ncbi.nlm.nih.gov/gene/7132" ref="ordinalpos=2&ncbi_uid=7132&link_uid=7132" style="font-size: 13.333333969116211px; line-height: 19.999780654907227px; white-space: nowrap; background-color: rgb(255, 255, 255);">TNFRSF1A</a></font></div><div><font face="Georgia"><span style="line-height: 19.999780654907227px; background-color: rgb(255, 255, 255);">NCBI Gene ID: </span><span style="background-color: rgb(255, 255, 255); font-size: 12.222222328186035px; line-height: 17.999801635742188px;">7132</span></font></div>

2017-10-13T15:42:38Z

<span style="line-height: 19.999780654907227px; background-color: rgb(255, 255, 255);"><font face="Georgia" size="2">Mitogen-activated protein kinase kinase kinase 1, E3 ubiquitin protein ligase</font></span><div><font face="Georgia" size="2"><span style="line-height: 19.999780654907227px; background-color: rgb(255, 255, 255);">UniProt ID: </span><a href="http://www.uniprot.org/uniprot/Q13233" style="text-decoration: none; background-color: rgb(255, 255, 255);">Q13233</a></font></div><div><font face="Georgia" size="2"><span style="line-height: 19.999780654907227px; background-color: rgb(255, 255, 255);">Gene Name: </span><a href="http://www.ncbi.nlm.nih.gov/gene/4214" ref="ordinalpos=4&ncbi_uid=4214&link_uid=4214" style="line-height: 19.999780654907227px; white-space: nowrap; background-color: rgb(255, 255, 255);">MAP3K1</a></font></div><div><font face="Georgia" size="2"><span style="line-height: 19.999780654907227px; background-color: rgb(255, 255, 255);">Gene ID: </span><span style="background-color: rgb(255, 255, 255); line-height: 17.999801635742188px;">4214</span></font></div>

2017-10-13T16:16:10Z

<font face="Georgia" size="2"><span style="line-height: 19.999780654907227px; background-color: rgb(255, 255, 255);">Inhibitor of kappa light polypeptide gene enhancer in B-cells, kinase beta [</span><em style="line-height: 19.999780654907227px; background-color: rgb(255, 255, 255);">Homo sapiens</em><span style="line-height: 19.999780654907227px; background-color: rgb(255, 255, 255);">(human)]</span></font><div><font face="Georgia" size="2"><span style="line-height: 19.999780654907227px; background-color: rgb(255, 255, 255);">UniProt ID: </span><a href="http://www.uniprot.org/uniprot/O14920" style="text-decoration: none; background-color: rgb(255, 255, 255);">O14920</a></font></div><div><font face="Georgia" size="2"><span style="line-height: 19.999780654907227px; background-color: rgb(255, 255, 255);">Gene Name: </span><a href="http://www.ncbi.nlm.nih.gov/gene/3551" ref="ordinalpos=6&ncbi_uid=3551&link_uid=3551" style="line-height: 19.999780654907227px; white-space: nowrap; background-color: rgb(255, 255, 255);">IKBKB</a></font></div><div><span style="line-height: 19.999780654907227px; background-color: rgb(255, 255, 255);"><font face="Georgia" size="2">NCBI Gene ID: 3551</font></span></div>

2015-11-15T19:54:34Z

<font face="Georgia"><span style="font-size: 13.333333969116211px; line-height: 19.999780654907227px; background-color: rgb(255, 255, 255);">TNFRSF1A-associated via death domain [</span><em style="font-size: 13.333333969116211px; line-height: 19.999780654907227px; background-color: rgb(255, 255, 255);">Homo sapiens</em><span style="font-size: 13.333333969116211px; line-height: 19.999780654907227px; background-color: rgb(255, 255, 255);"> (human)]</span><br/></font><div><font face="Georgia"><font size="2">UniProt Accession ID: </font><a href="http://www.uniprot.org/uniprot/Q15628" style="font-size: small; text-decoration: none; background-color: rgb(255, 255, 255);">Q15628</a></font></div><div><font face="Georgia">Gene Name: <a href="http://www.ncbi.nlm.nih.gov/gene/8717" ref="ordinalpos=1&ncbi_uid=8717&link_uid=8717" style="font-size: 13.333333969116211px; line-height: 19.999780654907227px; white-space: nowrap; background-color: rgb(255, 255, 255);"><span class="highlight">TRADD</span></a></font></div><div><font face="Georgia">NCBI Gene ID: <span style="background-color: rgb(255, 255, 255); font-size: 12.222222328186035px; line-height: 17.999801635742188px;">8717</span></font></div>

2017-10-13T15:42:38Z

<font face="Georgia" size="2"><span style="line-height: 19.999780654907227px; background-color: rgb(255, 255, 255);">CASP8 and FADD-like apoptosis regulator [</span><em style="line-height: 19.999780654907227px; background-color: rgb(255, 255, 255);">Homo sapiens</em><span style="line-height: 19.999780654907227px; background-color: rgb(255, 255, 255);">(human)]</span></font><div><font face="Georgia" size="2"><span style="line-height: 19.999780654907227px; background-color: rgb(255, 255, 255);">UniProt ID: </span><a href="http://www.uniprot.org/uniprot/O15519" style="text-decoration: none; background-color: rgb(255, 255, 255);">O15519</a></font></div><div><font face="Georgia" size="2"><span style="line-height: 19.999780654907227px; background-color: rgb(255, 255, 255);">Gene Name: </span><a href="http://www.ncbi.nlm.nih.gov/gene/8837" ref="ordinalpos=2&ncbi_uid=8837&link_uid=8837" style="line-height: 19.999780654907227px; white-space: nowrap; background-color: rgb(255, 255, 255);">CFLAR</a></font></div><div><font face="Georgia" size="2"><span style="line-height: 19.999780654907227px; background-color: rgb(255, 255, 255);">NCBI Gene ID: </span><span style="background-color: rgb(255, 255, 255); line-height: 17.999801635742188px;">8837</span></font></div>

2015-11-15T19:54:34Z

<font face="Georgia" size="2">Represents the release of apoptotic signals from the mitochondria [1]. </font>

2017-10-13T15:42:38Z

<div><font face="Georgia" size="2">Represents the inhibitor of nuclear factor kappa-B. </font></div><div><font face="Georgia" size="2"><span style="line-height: 16px; background-color: rgb(255, 255, 255);">Inhibitor of nuclear factor kappa-B kinase subunit beta </span></font></div><div><font face="Georgia" size="2"><span style="line-height: 16px; background-color: rgb(255, 255, 255);">UniProt ID: </span><span style="background-color: rgb(255, 255, 255);">O14920</span></font></div><div><font face="Georgia" size="2"><span style="background-color: rgb(255, 255, 255);">Gene Name: </span><a href="http://www.ncbi.nlm.nih.gov/gene/4793" ref="ordinalpos=7&ncbi_uid=4793&link_uid=4793" style="line-height: 19.999780654907227px; white-space: nowrap; background-color: rgb(255, 255, 255);">NFKBIB</a></font></div><div><font face="Georgia" size="2">NCBI Gene ID: <span style="background-color: rgb(255, 255, 255); line-height: 17.999801635742188px;">4793</span></font></div><div><span style="background-color: rgb(255, 255, 255); line-height: 17.999801635742188px;"><font face="Georgia" size="2"><br/></font></span></div><div style="font-size: 10pt; font-family: Arial, Verdana;"><span style="font-size: 16px; background-color: rgb(255, 255, 255);"><font face="Georgia"><br/></font></span></div><div style="font-size: 10pt; font-family: Arial, Verdana; font-weight: normal;"><strong style="font-family: sans-serif; font-size: 16px; background-color: rgb(255, 255, 255);"><br/></strong></div>

2017-10-13T15:51:06Z

<font face="Georgia"><span style="font-size: 13.333333969116211px; line-height: 19.999780654907227px; background-color: rgb(255, 255, 255);">Receptor (TNFRSF)-interacting serine-threonine kinase 1 [</span><em style="font-size: 13.333333969116211px; line-height: 19.999780654907227px; background-color: rgb(255, 255, 255);"><span class="highlight">Homo</span> sapiens</em><span style="font-size: 13.333333969116211px; line-height: 19.999780654907227px; background-color: rgb(255, 255, 255);">(human)]</span></font><div><font face="Georgia"><span style="font-size: 13.333333969116211px; line-height: 19.999780654907227px; background-color: rgb(255, 255, 255);">UniProt ID: </span><a href="http://www.uniprot.org/uniprot/Q13546" style="font-size: small; text-decoration: none; background-color: rgb(255, 255, 255);">Q13546</a></font></div><div><font face="Georgia"><span style="font-size: 13.333333969116211px; line-height: 19.999780654907227px; background-color: rgb(255, 255, 255);">Gene Name: </span><a href="http://www.ncbi.nlm.nih.gov/gene/8737" ref="ordinalpos=1&ncbi_uid=8737&link_uid=8737" style="font-size: 13.333333969116211px; line-height: 19.999780654907227px; white-space: nowrap; background-color: rgb(255, 255, 255);">RIPK1</a></font></div><div><font face="Georgia"><span style="font-size: 13.333333969116211px; line-height: 19.999780654907227px; background-color: rgb(255, 255, 255);">NCBI Gene ID: </span><span style="background-color: rgb(255, 255, 255); font-size: 12.222222328186035px; line-height: 17.999801635742188px;">8737</span></font></div>

2017-10-13T16:16:10Z

<font face="Georgia" size="2"><span style="line-height: 18.88888931274414px; background-color: rgb(255, 255, 255);">Mitogen-activated protein kinase 8 [</span><em style="line-height: 18.88888931274414px; background-color: rgb(255, 255, 255);">Homo sapiens</em><span style="line-height: 18.88888931274414px; background-color: rgb(255, 255, 255);"> (human)]</span></font><div><font face="Georgia" size="2"><span style="line-height: 18.88888931274414px; background-color: rgb(255, 255, 255);">UniProt ID: </span><a href="http://www.uniprot.org/uniprot/P45983" style="text-decoration: none; background-color: rgb(255, 255, 255);">P45983</a></font></div><div><font face="Georgia" size="2"><span style="line-height: 18.88888931274414px; background-color: rgb(255, 255, 255);">Gene Name: </span><a href="http://www.ncbi.nlm.nih.gov/gene/5599" ref="ordinalpos=5&ncbi_uid=5599&link_uid=5599" style="line-height: 18.88888931274414px; white-space: nowrap; background-color: rgb(255, 255, 255);">MAPK8</a></font></div><div><font face="Georgia" size="2"><span style="line-height: 18.88888931274414px; background-color: rgb(255, 255, 255);">Gene ID: </span><span style="background-color: rgb(255, 255, 255); line-height: 17.77777862548828px;">5599</span></font></div>

2015-11-15T19:54:34Z

<font face="Georgia" size="2" style="background-color: rgb(255, 255, 255);"><span style="line-height: 18.88888931274414px;">Mitogen-activated protein kinase kinase kinase 14 [</span><em style="line-height: 18.88888931274414px;">Homo sapiens</em><span style="line-height: 18.88888931274414px;">(human)]</span></font><div><font face="Georgia" size="2" style="background-color: rgb(255, 255, 255);"><span style="line-height: 18.88888931274414px;">UniProt ID: </span><a href="http://www.uniprot.org/uniprot/Q99558" style="text-decoration: none;">Q99558</a></font></div><div><font face="Georgia" size="2" style="background-color: rgb(255, 255, 255);"><span style="line-height: 18.88888931274414px;">Gene Name: </span><a href="http://www.ncbi.nlm.nih.gov/gene/9020" ref="ordinalpos=3&ncbi_uid=9020&link_uid=9020" style="line-height: 18.88888931274414px; white-space: nowrap;">MAP3K14</a></font></div><div><font face="Georgia" size="2" style="background-color: rgb(255, 255, 255);"><span style="line-height: 18.88888931274414px;">Gene ID:</span><span style="line-height: 17.77777862548828px;">9020</span></font></div>

2015-11-15T19:54:34Z

<font face="Georgia" size="2">Represents damage to DNA [1]. </font>

2017-10-13T15:24:03Z

<font face="Georgia" size="2"><span style="line-height: 19.999780654907227px; background-color: rgb(255, 255, 255);">Mitogen-activated protein kinase kinase 4 [</span><em style="line-height: 19.999780654907227px; background-color: rgb(255, 255, 255);">Homo sapiens</em><span style="line-height: 19.999780654907227px; background-color: rgb(255, 255, 255);"> (human)]</span></font><div><font face="Georgia" size="2"><span style="line-height: 19.999780654907227px; background-color: rgb(255, 255, 255);">UniProt ID: </span><a href="http://www.uniprot.org/uniprot/P45985" style="text-decoration: none; background-color: rgb(255, 255, 255);">P45985</a></font></div><div><font face="Georgia" size="2"><span style="line-height: 19.999780654907227px; background-color: rgb(255, 255, 255);">Gene Name: </span><a href="http://www.ncbi.nlm.nih.gov/gene/6416" ref="ordinalpos=2&ncbi_uid=6416&link_uid=6416" style="line-height: 19.999780654907227px; white-space: nowrap; background-color: rgb(255, 255, 255);">MAP2K4</a></font></div><div><span style="line-height: 19.999780654907227px; background-color: rgb(255, 255, 255);"><font face="Georgia" size="2">NCBI Gene ID: 6416</font></span></div>

2015-11-15T19:54:34Z

<font size="2" face="Georgia">Referring to p65(RelA):p50\r\nheterodimers in this context [1]. </font><div style="font-style: normal; font-variant: normal; font-weight: normal; line-height: normal;"><font face="Georgia" size="2"><span class="highlight" style="line-height: 18.88888931274414px; background-color: rgb(255, 255, 255);">Nuclear</span><span style="line-height: 18.88888931274414px; background-color: rgb(255, 255, 255);"> </span><span class="highlight" style="line-height: 18.88888931274414px; background-color: rgb(255, 255, 255);">factor</span><span style="line-height: 18.88888931274414px; background-color: rgb(255, 255, 255);"> of kappa light polypeptide gene enhancer in B-cells 1 [</span><em style="line-height: 18.88888931274414px; background-color: rgb(255, 255, 255);">Homo sapiens</em><span style="line-height: 18.88888931274414px; background-color: rgb(255, 255, 255);"> (human)]</span></font><div><font face="Georgia" size="2"><span style="line-height: 18.88888931274414px; background-color: rgb(255, 255, 255);">UniProt ID: </span><a href="http://www.uniprot.org/uniprot/P19838" style="text-decoration: none; background-color: rgb(255, 255, 255);">P19838</a></font></div><div><font face="Georgia" size="2"><span style="line-height: 18.88888931274414px; background-color: rgb(255, 255, 255);">Gene Name: </span><a href="http://www.ncbi.nlm.nih.gov/gene/4790" ref="ordinalpos=6&ncbi_uid=4790&link_uid=4790" style="line-height: 18.88888931274414px; white-space: nowrap; background-color: rgb(255, 255, 255);">NFKB1</a></font></div><div><font face="Georgia" size="2"><span style="line-height: 18.88888931274414px; background-color: rgb(255, 255, 255);">Gene ID:</span><span style="background-color: rgb(255, 255, 255); line-height: 17.77777862548828px;">4790</span></font></div><div><font face="Georgia" size="2"><span style="line-height: 18.88888931274414px; background-color: rgb(255, 255, 255);">v-rel avian reticuloendotheliosis viral oncogene homolog A [</span><em style="line-height: 18.88888931274414px; background-color: rgb(255, 255, 255);">Homo sapiens</em><span style="line-height: 18.88888931274414px; background-color: rgb(255, 255, 255);"> (human)]</span></font></div><div><font face="Georgia" size="2"><span style="line-height: 18.88888931274414px; background-color: rgb(255, 255, 255);">UniProt ID: </span><a href="http://www.uniprot.org/uniprot/Q04206" style="text-decoration: none; background-color: rgb(255, 255, 255);">Q04206</a></font></div><div><font face="Georgia" size="2"><span style="line-height: 18.88888931274414px; background-color: rgb(255, 255, 255);">Gene Name: </span><a href="http://www.ncbi.nlm.nih.gov/gene/5970" ref="ordinalpos=1&ncbi_uid=5970&link_uid=5970" style="line-height: 18.88888931274414px; white-space: nowrap; background-color: rgb(255, 255, 255);">RELA</a></font></div><div><font face="Georgia" size="2"><span style="line-height: 18.88888931274414px; background-color: rgb(255, 255, 255);">Gene ID:</span><span style="background-color: rgb(255, 255, 255); line-height: 17.77777862548828px;">5970</span></font></div></div>

2017-10-13T15:51:06Z

<br/>

2015-11-15T19:54:34Z

<font face="Georgia" size="2"><span style="line-height: 19.999780654907227px; background-color: rgb(255, 255, 255);">BCL2-like 1 [</span><em style="line-height: 19.999780654907227px; background-color: rgb(255, 255, 255);">Homo sapiens</em><span style="line-height: 19.999780654907227px; background-color: rgb(255, 255, 255);"> (human)]</span></font><div><font face="Georgia" size="2"><span style="line-height: 19.999780654907227px; background-color: rgb(255, 255, 255);">UniProt ID: </span><a href="http://www.uniprot.org/uniprot/Q07817" style="text-decoration: none; background-color: rgb(255, 255, 255);">Q07817</a><span style="background-color: rgb(255, 255, 255); line-height: 19.999780654907227px;"> </span></font></div><div><font face="Georgia" size="2"><span style="line-height: 19.999780654907227px; background-color: rgb(255, 255, 255);">Gene Name: </span><a href="http://www.ncbi.nlm.nih.gov/gene/598" ref="ordinalpos=2&ncbi_uid=598&link_uid=598" style="line-height: 19.999780654907227px; white-space: nowrap; background-color: rgb(255, 255, 255);">BCL2L1</a></font></div><div><font face="Georgia" size="2"><span style="line-height: 19.999780654907227px; background-color: rgb(255, 255, 255);">Gene ID: </span><span style="background-color: rgb(255, 255, 255); line-height: 17.999801635742188px;">598</span></font></div>

2017-10-13T15:51:06Z

<span style="line-height: 16px; background-color: rgb(255, 255, 255);"><font face="Georgia">AN1-type zinc finger protein 5</font></span><div><font face="Georgia"><span style="line-height: 16px; background-color: rgb(255, 255, 255);">UniProt ID: </span><span style="background-color: rgb(255, 255, 255);">O76080</span></font></div><div><span style="background-color: rgb(255, 255, 255);"><font face="Georgia"><br/></font></span></div><div><font face="Georgia"><span style="background-color: rgb(255, 255, 255);">alternative names:</span><span style="background-color: rgb(255, 255, 255); line-height: 16px;">Zinc finger A20 domain-containing protein 2</span></font></div><div style="font-size: 10pt; font-family: Arial, Verdana;"><br/></div>

2017-10-13T15:42:38Z

<font face="Georgia" size="2"><span class="highlight" style="line-height: 19.999780654907227px; background-color: rgb(255, 255, 255);">Caspase</span><span style="line-height: 19.999780654907227px; background-color: rgb(255, 255, 255);"> </span><span class="highlight" style="line-height: 19.999780654907227px; background-color: rgb(255, 255, 255);">3</span><span style="line-height: 19.999780654907227px; background-color: rgb(255, 255, 255);">, apoptosis-related cysteine peptidase [</span><em style="line-height: 19.999780654907227px; background-color: rgb(255, 255, 255);">Homo sapiens</em><span style="line-height: 19.999780654907227px; background-color: rgb(255, 255, 255);">(human)]</span></font><div><font face="Georgia" size="2"><span style="line-height: 19.999780654907227px; background-color: rgb(255, 255, 255);">UniProt ID: </span><a href="http://www.uniprot.org/uniprot/P42574" style="text-decoration: none; background-color: rgb(255, 255, 255);">P42574</a></font></div><div><font face="Georgia" size="2"><span style="line-height: 19.999780654907227px; background-color: rgb(255, 255, 255);">Gene Name: </span><a href="http://www.ncbi.nlm.nih.gov/gene/836" ref="ordinalpos=2&ncbi_uid=836&link_uid=836" style="line-height: 19.999780654907227px; white-space: nowrap; background-color: rgb(255, 255, 255);">CASP3</a></font></div><div><font face="Georgia" size="2"><span style="line-height: 19.999780654907227px; background-color: rgb(255, 255, 255);">NCBI Gene ID: </span><span style="background-color: rgb(255, 255, 255); line-height: 17.999801635742188px;">836</span></font></div>

2017-10-13T15:42:38Z

<font face="Georgia" size="2"><span class="highlight" style="line-height: 19.999780654907227px; background-color: rgb(255, 255, 255);">Caspase</span><span style="line-height: 19.999780654907227px; background-color: rgb(255, 255, 255);"> 8, apoptosis-related cysteine peptidase [</span><em style="line-height: 19.999780654907227px; background-color: rgb(255, 255, 255);">Homo sapiens</em><span style="line-height: 19.999780654907227px; background-color: rgb(255, 255, 255);">(human)]</span></font><div><font face="Georgia" size="2"><span style="line-height: 19.999780654907227px; background-color: rgb(255, 255, 255);">UniProt ID: </span><a href="http://www.uniprot.org/uniprot/Q14790" style="text-decoration: none; background-color: rgb(255, 255, 255);">Q14790</a></font></div><div><font face="Georgia" size="2"><span style="line-height: 19.999780654907227px; background-color: rgb(255, 255, 255);">Gene Name: </span><a href="http://www.ncbi.nlm.nih.gov/gene/841" ref="ordinalpos=2&ncbi_uid=841&link_uid=841" style="line-height: 19.999780654907227px; white-space: nowrap; background-color: rgb(255, 255, 255);">CASP8</a></font></div><div><span style="line-height: 19.999780654907227px; background-color: rgb(255, 255, 255);"><font face="Georgia" size="2">NCBI Gene ID: 841</font></span></div>

2017-10-13T15:42:38Z

programmed cell death

2017-10-13T15:24:03Z

<font face="Georgia" size="2"><span class="highlight" style="line-height: 19.999780654907227px; background-color: rgb(255, 255, 255);">Caspase</span><span style="line-height: 19.999780654907227px; background-color: rgb(255, 255, 255);"> </span><span class="highlight" style="line-height: 19.999780654907227px; background-color: rgb(255, 255, 255);">6</span><span style="line-height: 19.999780654907227px; background-color: rgb(255, 255, 255);">, apoptosis-related cysteine peptidase [</span><em style="line-height: 19.999780654907227px; background-color: rgb(255, 255, 255);">Homo sapiens</em><span style="line-height: 19.999780654907227px; background-color: rgb(255, 255, 255);">(human)]</span></font><div style="line-height: normal;"><font face="Georgia" size="2"><span style="line-height: 19.999780654907227px; background-color: rgb(255, 255, 255);">UniProt ID: </span><a href="http://www.uniprot.org/uniprot/P55212" style="text-decoration: none; background-color: rgb(255, 255, 255);">P55212</a></font></div><div><font face="Georgia" size="2"><span style="line-height: 19.999780654907227px; background-color: rgb(255, 255, 255);">Gene Name: </span><a href="http://www.ncbi.nlm.nih.gov/gene/839" ref="ordinalpos=2&ncbi_uid=839&link_uid=839" style="line-height: 19.999780654907227px; white-space: nowrap; background-color: rgb(255, 255, 255);">CASP6</a></font></div><div><font face="Georgia" size="2"><span style="line-height: 19.999780654907227px; background-color: rgb(255, 255, 255);">NCABI Gene ID: </span><span style="background-color: rgb(255, 255, 255); line-height: 17.999801635742188px;">839</span></font></div>

2017-10-13T15:42:38Z

<font face="Georgia" size="2"><span style="line-height: 19.999780654907227px; background-color: rgb(255, 255, 255);">Tumor protein </span><span class="highlight" style="line-height: 19.999780654907227px; background-color: rgb(255, 255, 255);">p53</span><span style="line-height: 19.999780654907227px; background-color: rgb(255, 255, 255);">[</span><em style="line-height: 19.999780654907227px; background-color: rgb(255, 255, 255);">Homo sapiens</em><span style="line-height: 19.999780654907227px; background-color: rgb(255, 255, 255);">(human)]</span></font><div><font face="Georgia" size="2"><span style="line-height: 19.999780654907227px; background-color: rgb(255, 255, 255);">UniProt ID: </span><a href="http://www.uniprot.org/uniprot/P04637" style="text-decoration: none; background-color: rgb(255, 255, 255);">P04637</a></font></div><div><font face="Georgia" size="2"><span style="line-height: 19.999780654907227px; background-color: rgb(255, 255, 255);">Gene Name: </span><a href="http://www.ncbi.nlm.nih.gov/gene/7157" ref="ordinalpos=2&ncbi_uid=7157&link_uid=7157" style="line-height: 19.999780654907227px; white-space: nowrap; background-color: rgb(255, 255, 255);">TP53</a></font></div><div><font face="Georgia" size="2"><span style="line-height: 19.999780654907227px; background-color: rgb(255, 255, 255);">NCBI Gene ID: </span><span style="background-color: rgb(255, 255, 255); line-height: 17.999801635742188px;">7157</span></font></div>

2017-10-13T15:42:38Z

<div><font face="Georgia" size="2"><span class="highlight" style="line-height: 18.88888931274414px; background-color: rgb(255, 255, 255);">Phosphatidylinositol</span><span style="line-height: 18.88888931274414px; background-color: rgb(255, 255, 255);">-4,5-bisphosphate 3-kinase, catalytic subunit alpha [</span><em style="line-height: 18.88888931274414px; background-color: rgb(255, 255, 255);">Homo sapiens</em><span style="line-height: 18.88888931274414px; background-color: rgb(255, 255, 255);">(human)]</span></font></div><div><font face="Georgia" size="2"><span style="line-height: 18.88888931274414px; background-color: rgb(255, 255, 255);">UniProt ID: </span><a href="http://www.uniprot.org/uniprot/P42336" style="text-decoration: none; background-color: rgb(255, 255, 255);">P42336</a></font></div><div><font face="Georgia" size="2"><span style="line-height: 18.88888931274414px; background-color: rgb(255, 255, 255);">Gene Name: </span><a href="http://www.ncbi.nlm.nih.gov/gene/5290" ref="ordinalpos=1&ncbi_uid=5290&link_uid=5290" style="background-color: rgb(255, 255, 255); line-height: 18.88888931274414px; white-space: nowrap;">PIK3CA</a></font></div><div><font face="Georgia" size="2"><span style="line-height: 18.88888931274414px; background-color: rgb(255, 255, 255);">Gene ID: </span><span style="background-color: rgb(255, 255, 255); line-height: 17.77777862548828px;">5290</span></font></div>

2015-11-15T19:54:34Z

<font face="Georgia" size="2"><span style="line-height: 18.88888931274414px; background-color: rgb(255, 255, 255);">BCL2-associated agonist of cell death [</span><em style="line-height: 18.88888931274414px; background-color: rgb(255, 255, 255);">Homo sapiens</em><span style="line-height: 18.88888931274414px; background-color: rgb(255, 255, 255);"> (human)]</span></font><div><font face="Georgia" size="2"><span style="line-height: 18.88888931274414px; background-color: rgb(255, 255, 255);">UniProt ID: </span><a href="http://www.uniprot.org/uniprot/Q92934" style="text-decoration: none; background-color: rgb(255, 255, 255);">Q92934</a></font></div><div><font face="Georgia" size="2"><span style="line-height: 18.88888931274414px; background-color: rgb(255, 255, 255);">Gene Name: </span><a href="http://www.ncbi.nlm.nih.gov/gene/572" ref="ordinalpos=1&ncbi_uid=572&link_uid=572" style="line-height: 18.88888931274414px; white-space: nowrap; background-color: rgb(255, 255, 255);"><span class="highlight">BAD</span></a></font></div><div><span style="line-height: 18.88888931274414px; background-color: rgb(255, 255, 255);"><font face="Georgia" size="2">Gene ID: 572</font></span></div>

2015-11-15T19:54:34Z

<font face="Georgia" size="2" style="font-style: normal; font-variant: normal; font-weight: normal; line-height: normal;">This node represents the apoptosome complex [1]. Information about the apoptosome at (</font><font face="Georgia" size="2"><a href="http://www.ncbi.nlm.nih.gov/mesh/?term=apoptosome">http://www.ncbi.nlm.nih.gov/mesh/?term=apoptosome</a>). </font>

2015-11-15T19:54:34Z

<font face="Georgia" size="2"><span class="highlight" style="line-height: 19.999780654907227px; background-color: rgb(255, 255, 255);">MDM2</span><span style="line-height: 19.999780654907227px; background-color: rgb(255, 255, 255);"> oncogene, E3 ubiquitin protein ligase [</span><em style="line-height: 19.999780654907227px; background-color: rgb(255, 255, 255);">Homo sapiens</em><span style="line-height: 19.999780654907227px; background-color: rgb(255, 255, 255);"> (human)]</span></font><div><font face="Georgia" size="2"><span style="line-height: 19.999780654907227px; background-color: rgb(255, 255, 255);">UniProt ID: </span><a href="http://www.uniprot.org/uniprot/Q00987" style="text-decoration: none; background-color: rgb(255, 255, 255);">Q00987</a></font></div><div><font face="Georgia" size="2"><span style="line-height: 19.999780654907227px; background-color: rgb(255, 255, 255);">Gene Name: </span><a href="http://www.ncbi.nlm.nih.gov/gene/4193" ref="ordinalpos=1&ncbi_uid=4193&link_uid=4193" style="line-height: 19.999780654907227px; white-space: nowrap; background-color: rgb(255, 255, 255);"><span class="highlight">MDM2</span></a></font></div><div><span style="line-height: 19.999780654907227px; background-color: rgb(255, 255, 255);"><font face="Georgia" size="2">NCBI Gene ID: 4193</font></span></div>

2015-11-15T19:54:34Z

<font face="Georgia" size="2"><span class="highlight" style="line-height: 19.999780654907227px; background-color: rgb(255, 255, 255);">Caspase</span><span style="line-height: 19.999780654907227px; background-color: rgb(255, 255, 255);"> </span><span class="highlight" style="line-height: 19.999780654907227px; background-color: rgb(255, 255, 255);">12</span><span style="line-height: 19.999780654907227px; background-color: rgb(255, 255, 255);">(gene/pseudogene) [</span><em style="line-height: 19.999780654907227px; background-color: rgb(255, 255, 255);">Homo sapiens</em><span style="line-height: 19.999780654907227px; background-color: rgb(255, 255, 255);">(human)]</span></font><div><font face="Georgia" size="2"><span style="line-height: 19.999780654907227px; background-color: rgb(255, 255, 255);">UniProt ID: </span><a href="http://www.uniprot.org/uniprot/Q6UXS9" style="text-decoration: none; background-color: rgb(255, 255, 255);">Q6UXS9</a></font></div><div><font face="Georgia" size="2"><span style="line-height: 19.999780654907227px; background-color: rgb(255, 255, 255);">Gene Name: </span><a href="http://www.ncbi.nlm.nih.gov/gene/100506742" ref="ordinalpos=5&ncbi_uid=100506742&link_uid=100506742" style="line-height: 19.999780654907227px; white-space: nowrap; background-color: rgb(255, 255, 255);">CASP12</a></font></div><div><font face="Georgia" size="2"><span style="line-height: 19.999780654907227px; background-color: rgb(255, 255, 255);">NCBI Gene ID: </span><span style="background-color: rgb(255, 255, 255); line-height: 17.999801635742188px;">100506742</span></font></div>

2015-11-15T19:54:34Z

<font size="2" style="font-style: normal;" face="Georgia">baculoviral IAP repeat-containing 2 (BIRC2)</font><div style="font-style: normal;"><font face="Georgia"><font size="2">UniProt Accession ID: Q13490</font><font size="2"><br/></font></font><div><font size="2" face="Georgia"><br/></font></div><div><font face="Georgia" size="2">baculoviral IAP repeat-containing 3 (BIRC3)</font></div><div><font face="Georgia" size="2">UniProt Accession ID: Q13489</font></div><div><font face="Georgia" size="2"><br/></font></div><div><font face="Georgia" size="2">baculoviral IAP repeat-containing 4 (BIRC4)</font></div></div><div style="font-style: normal;"><font face="Georgia" size="2">UniProt Accession ID: P98170</font></div><div style="font-style: normal;"><font face="Georgia" size="2"><br/></font></div><div><font face="Georgia" size="2">In the <em>Apoptosis Network</em>, IAP represents inhibitors of apoptosis [1].</font></div><div><font face="Georgia" size="2"><br/></font></div><div><font face="Georgia" size="2">In Survival Signaling 2008 and 2011, IAP represents inhibitors of apoptosis.</font></div>

2017-10-13T15:51:06Z

<font face="Georgia" size="2"><span class="highlight" style="line-height: 19.999780654907227px; background-color: rgb(255, 255, 255);">Caspase</span><span style="line-height: 19.999780654907227px; background-color: rgb(255, 255, 255);"> </span><span class="highlight" style="line-height: 19.999780654907227px; background-color: rgb(255, 255, 255);">9</span><span style="line-height: 19.999780654907227px; background-color: rgb(255, 255, 255);">, apoptosis-related cysteine peptidase [</span><em style="line-height: 19.999780654907227px; background-color: rgb(255, 255, 255);">Homo sapiens</em><span style="line-height: 19.999780654907227px; background-color: rgb(255, 255, 255);">(human)]</span></font><div><font face="Georgia" size="2"><span style="line-height: 19.999780654907227px; background-color: rgb(255, 255, 255);">UniProt ID: </span><a href="http://www.uniprot.org/uniprot/P55211" style="text-decoration: none; background-color: rgb(255, 255, 255);">P55211</a></font></div><div><font face="Georgia" size="2"><span style="line-height: 19.999780654907227px; background-color: rgb(255, 255, 255);">Gene Name: </span><a href="http://www.ncbi.nlm.nih.gov/gene/842" ref="ordinalpos=1&ncbi_uid=842&link_uid=842" style="line-height: 19.999780654907227px; white-space: nowrap; background-color: rgb(255, 255, 255);">CASP9</a></font></div><div><span style="line-height: 19.999780654907227px; background-color: rgb(255, 255, 255);"><font face="Georgia" size="2">NCBI Gene ID: 842</font></span></div>

2015-11-15T19:54:34Z

<div><font face="Georgia" size="2"><span style="line-height: 19.999780654907227px; background-color: rgb(255, 255, 255);">BH3 interacting domain death agonist [</span><em style="line-height: 19.999780654907227px; background-color: rgb(255, 255, 255);">Homo sapiens</em><span style="line-height: 19.999780654907227px; background-color: rgb(255, 255, 255);"> (human)]</span></font></div><div><font face="Georgia" size="2">UniProt Accession ID: <a href="http://www.uniprot.org/uniprot/P55957" style="text-decoration: none; background-color: rgb(255, 255, 255);">P55957<br/></a><font>Gene Name: </font><a href="http://www.ncbi.nlm.nih.gov/gene/637" ref="ordinalpos=1&ncbi_uid=637&link_uid=637" style="color: rgb(100, 42, 143); line-height: 19.999780654907227px; white-space: nowrap; background-color: rgb(255, 255, 255);"><span class="highlight">BID</span></a></font></div><div><font face="Georgia" size="2">Gene ID: 637</font></div>

2017-10-13T15:42:38Z

<div><font face="Georgia" size="2"><span style="line-height: 19.999780654907227px; background-color: rgb(255, 255, 255);">Fas (TNFRSF6)-associated via death domain [</span><em style="line-height: 19.999780654907227px; background-color: rgb(255, 255, 255);">Homo sapiens</em><span style="line-height: 19.999780654907227px; background-color: rgb(255, 255, 255);">(human)]</span></font></div><font face="Georgia" size="2">Uniprot ID: Q13158</font><div><font face="Georgia" size="2">Gene Name: <a href="http://www.ncbi.nlm.nih.gov/gene/8772" ref="ordinalpos=1&ncbi_uid=8772&link_uid=8772" style="line-height: 19.999780654907227px; white-space: nowrap; background-color: rgb(255, 255, 255);"><span class="highlight">FADD</span></a></font></div><div><font face="Georgia" size="2">NCBI Gene ID: <span style="background-color: rgb(255, 255, 255); line-height: 17.999801635742188px;">8772</span></font></div>

2017-10-13T15:42:38Z

<font face="Georgia">PI3K and pip2 are both required to activate pip3. PTEN inhibits pip3 and is dominant over all activators [1]. </font>

<font face="Georgia">PTEN dephosphorylates pip3 and thereby degrades it [1,3,4].</font>

<font face="Georgia" size="2">PI3K produces pip3 from pip2 [1,2]. </font>

<span style="font-family: Georgia; font-size: small;">PI3K produces pip3 from pip2 [1,2]. </span>

S_33 1 S_6 1 S_4 1

<font face="Georgia" size="2">GF activates GFR [1]. </font>

<font face="Georgia" size="2">Growth factors activate growth factor receptors [1]. </font>

S_25 1

<font face="Georgia" size="2">Caspase 7 is activated by APC or caspase 8. IAP is a negative regulator of caspase 7 and is dominant over both activators [1]. </font>

<font face="Georgia" size="2">IAP is an inhibitor of caspase 7 [1,2,3]. </font>

<span style="font-family: Georgia; font-size: small;">Caspase 7 is activated by caspase 8 [1, 2, 3]. </span>

<font face="Georgia" size="2">Caspase 7 is activated by APC [1, 2, 3]. </font>

S_28 1 S_38 1 S_35 1 S_38 1

<span style="font-family: Georgia;">p53 activates PTEN [1]. </span>

<font face="Georgia">p53 activates PTEN [1,2,3]. </font>

S_32 1

<span style="font-family: Georgia;">TNF activates TNFR2 [1]. </span>

<font face="Georgia">TNF activates TNFR2 [1,2]. </font>

S_29 1

<span style="font-family: Georgia; font-size: small;">GFR activates PIP2 [1]. </span>

<font face="Georgia" size="2">GFR activates PIP2 [1,2]. </font>

S_2 1

<font face="Georgia" size="2">p53 activates Apaf1 [1]. </font>

<font face="Georgia" size="2">The central regulator p53 generates pro-apoptotic output via Apaf1 [1,2,3,4]. </font>

S_32 1

<font face="Georgia">TNFR2 activates TRAF2 [1]. </font>

RIP activates TRAF2.

Both RIP and TRAF2 are required for IKK activation.

<font face="Georgia">TNFR2 activates TRAF2 [1,2]. </font>

S_5 1 S_17 1

<span style="font-family: Georgia;">TRADD activates TRAF [1]. </span>

<font face="Georgia">TRADD activates TRAF [1,2]. </font>

S_13 1

<font face="Georgia">TNFR1 is activated by TNF [1]. </font>

<font face="Georgia">TNFR1 is activated by TNF [1,2]. </font>

S_29 1

<font face="Georgia" size="2">RIP activates Mekk1 [1]. </font>

RIP phosphorylates MEKK1 at Ser-957 and Ser-994.

S_17 1

<font face="Georgia" size="2">AKT and NIK each activate IKK, while A20 inhibits IKK and is dominant over both activators [1]. </font>

<span style="font-family: Georgia; font-size: small;">AKT activates IKK [1]. </span>

<span style="font-family: Georgia; font-size: small;">NIK activates IKK [1]. </span>

<font face="Georgia" size="2">A20 inhibits IKK [1]. </font>

S_19 1 S_26 1 S_23 1 S_26 1

<span style="font-family: Georgia;">TNFR1 activates TRADD [1]. </span>

<font face="Georgia">TNFR1 activates TRADD [1,2]. </font>

S_10 1

<font face="Georgia" size="2">TRAF activates cFLIP [1]. </font>

S_9 1

<font face="Georgia" size="2">BID activates Mito, while BclX deactivates Mito and is dominant over BID [1]. </font>

<font face="Georgia" size="2">BID generates a pro-apoptotic signal [1,2,3,4]. </font>

<font face="Georgia" size="2">BclX prevents the release of apoptotic signals from the mitochondria [1]. </font>

S_40 1 S_24 1

<font face="Georgia" size="2">NFkB activates ikb and IKK deactivates ikb and is dominant over the effect of NFkB [1]. </font>

<font face="Georgia" size="2">The activated IkB kinase complex (IKK) removes the inhibitor of NFkB (IKB) [1,4,5,6,7].</font>

<font face="Georgia" size="2">NfkB exerts negative feedback regulation on its own production by activating ikb [1,2,3].</font>

S_22 1 S_12 1

<span style="font-family: Georgia;">TRADD activates RIP [1].</span>

<font face="Georgia">TRADD activates RIP [1,2,3].</font>

S_13 1

<font face="Georgia" size="2">JNKK activates JNK [1]. </font>

<font face="Georgia" size="2">JNKK activates JNK [1,2,3]. </font>

S_21 1

<span style="font-family: Georgia; font-size: small;">TRAF2 activates NIK [1]. </span>

<font face="Georgia" size="2">TRAF2 activates NIK [1]. </font>

S_8 1

<font face="Georgia" size="2">Cas3 activates DNADamage [1]. </font>

<font face="Georgia" size="2">DNA Damage Event is activated by Cas3 after two time units have occurred. According to Mai and Liu, "This node is\r\nalways set to the OFF state unless the caspase 3 node has been in\r\nthe ON state in previous two successive steps: only when both\r\nS<sub>Cas3</sub>(t=1) = ON and S<sub>Cas3</sub>(t) = ON, S<sub>DNA Damage Event</sub>(t+1) = ON,\r\notherwise S<sub>DNA Damage Event</sub>(t+1) = OFF [1]."

S_27 1

<font face="Georgia">MEKK1 activates JNKK, while AKT inhibits JNKK and is dominant over MEKK1 [1]. </font>

<font face="Georgia">AKt inhibits JNKK [1]. </font>

<font face="Georgia" size="2">MEKK1 activates JNKK [1,2,3].</font>

S_11 1 S_23 1

<span style="font-family: Georgia; font-size: small;">IkB inactivates NFkB [1].</span>

<font face="Georgia" size="2">IkB inactivates NFkB [1,2,3].</font>

S_16 1

<font face="Georgia" size="2">PIP3 activates Akt [1, 2]. </font>

\r\n \r\n \r\n \r\n <div class="page" title="Page 2">\r\n <div class="layoutArea">\r\n <div class="column">\r\n <p><font face="Georgia" size="2">PIP3 activates Akt [1,2]. </font></p>\r\n </div>\r\n </div>\r\n </div>

S_1 1

<font face="Georgia" size="2">NFkB activates BclX, while both BAD and p53 are inhibitor s of BclX and are dominant over NfkB [1]. </font>

<font face="Georgia" size="2">NFkB activates BclX [1,2,3]. </font>

<font face="Georgia" size="2">BAD creates pro-apoptotic effects by inhibiting BclX [1]. </font>

<font face="Georgia" size="2">p53 inhibits BclX [1]. </font>

S_22 1 S_32 1 S_34 1

<font face="Georgia" size="2">NFkB inhibits A20 [1].</font>

NFkB exerts negative feedback regulation on its own inducing pathway via activating A20 and IkB [1,2,3].

S_22 1

<font face="Georgia" size="2">APC, Cas6, and Cas8 can each activate Cas3. IAP is a negative regulator of Cas3 and is dominant over all positive regulators [1]. </font>

\r\n \r\n \r\n <div class="page" title="Page 3">\r\n <div class="layoutArea">\r\n <div class="column">\r\n <p><font face="Georgia" size="2">IAP is a negative regulator of Cas3 [1,2,3]. </font></p>\r\n </div>\r\n </div>\r\n </div>

<span style="background-color: rgb(255, 255, 255);"><font face="Georgia" size="2">Caspase 8 is can activate caspase 3 [1,2,3]. </font></span>

\r\n \r\n \r\n <div class="page" title="Page 3">\r\n <div class="layoutArea">\r\n <div class="column">\r\n <p><font face="Georgia" size="2">Caspase 6 is performs a positive feedback on Caspase 3 [1,2,3]. </font></p>\r\n </div>\r\n </div>\r\n </div>

\r\n \r\n \r\n <div class="page" title="Page 3">\r\n <div class="layoutArea">\r\n <div class="column">\r\n <p><font face="Georgia" size="2" style="background-color: rgb(255, 255, 255);">The activation of caspase 3 involves APC [1,2,3].  </font></p>\r\n </div>\r\n </div>\r\n </div>

S_35 1 S_38 1 S_31 1 S_38 1 S_28 1 S_38 1

<font face="Georgia" size="2">Cas6 and FADD can each independently activate cas8. cFlip is an inhibitor of cas8 and is dominant over both activators [1]. </font>

<font face="Georgia" size="2">cFLIP is an inhibitory protein of caspase 8 [1,3,4,5,6,7]. </font>

<font face="Georgia" size="2">Activation of FADD causes the activation of caspase 8 [1,2]. </font>

<font face="Georgia" size="2">Caspase 6 has a positive feedback effect upon caspase 8 [1,8,9]. </font>

S_41 1 S_14 1 S_31 1 S_14 1

DNADamageEvent activates Apoptosis.

If DNA damage persists, the cell will undergo apoptosis. This is modeled by having DNADamageEvent activate Apoptosis only if DNADamageEvent is ON for 20 continuous steps.

S_20 1

<font face="Georgia" size="2">Cas3 is positive regulator of Cas6 and IAP is a negative regulator of Cas6 and is dominant over Cas3 [1]. </font>

<font face="Georgia" size="2">Cas3 is a positive regulator of Cas6 [1]. </font>

<font face="Georgia" size="2">IAP is a negative regulator of Cas6 [1]. </font>

S_27 1 S_38 1

<font face="Georgia">DNADamageEvent and JNK each activate p53. Mdm2 inhibits p53 and is dominant over both activators [1]. </font>

<font face="Georgia">Mdm2 inhibits p53 [1,4,5,6].</font>

<font face="Georgia">DNADamageEvent activates p53 [1,4,5,6].</font>

<font face="Georgia">JNK activates p53 through the mitogen-activated protein kinase cascade [1,2,3].</font>

S_20 1 S_36 1 S_18 1 S_36 1

<span style="font-family: Georgia; font-size: small;">GFR activates PI3K [1]. </span>

<font size="2" face="Georgia">GFR activates PI3K [1,2]. </font>

S_2 1

\r\n \r\n \r\n <div class="page" title="Page 3">\r\n <div class="layoutArea">\r\n <div class="column">\r\n <p><font face="Georgia" size="2">BAD is activated by p53 and inactivated by AKT [1]. </font></p>\r\n </div>\r\n </div>\r\n </div>

<font face="Georgia" size="2">BAD is suppressed by pro-survival signals from Akt  [1,2]. </font>

<font face="Georgia" size="2">BAD is activated by pro-apoptotic signals from p53 [1,2]. </font>

S_32 1 S_23 1

\r\n \r\n \r\n <div class="page" title="Page 3">\r\n <div class="layoutArea">\r\n <div class="column">\r\n <p><font face="Georgia" size="2">Apaf1, Casp9 and Mito are all required to activate APC. IAP inhibits APC [1]. </font></p>\r\n </div>\r\n </div>\r\n </div>

<font face="Georgia" size="2">APC requires Cas9 to be activated [1]. </font>

<font face="Georgia" size="2">Inhibitors of apoptosis inhibit APC [1]. </font>

<font face="Georgia" size="2">The mitochondrion releases other factors that overcome the inhibition of IAP and are collectively called Mito. These suppress the inhibition of IAP and thus activate APC [1]. </font>

<font face="Georgia" size="2">APC requires Apaf1 to be activated [1]. </font>

S_39 1 S_15 1 S_7 1 S_38 1

<font face="Georgia" size="2">AKt and p53 each activate Mdm2 [1].</font>

<font face="Georgia" size="2">AKT activates Mdm2 [1]. </font>

<span style="font-family: Georgia; font-size: small;">p53 activates Mdm2 [1]. </span>

S_32 1 S_23 1

<span style="font-family: Georgia; font-size: small;">Cas7 activates Cas12 [1]. </span>

<font face="Georgia" size="2">Cas7 activates Cas12 [1]. </font>

S_3 1

<span style="font-family: Georgia; font-size: small;">NFkB activates IAP. Mito can inhibit IAP and Cas3 and Cas6 jointly inhibit IAP. All inhibitors are dominant over activators[1]. </span>

<font face="Georgia" size="2">Cas3 and Cas6 jointly inhibit IAP [1]. </font>

<font face="Georgia" size="2">NFkB activates IAP [1,2,3].</font>

<font face="Georgia" size="2">The mitochondria component is a direct inhibitor of IAP [1]. </font>

<span style="font-family: Georgia; font-size: small;">Cas3 and Cas6 jointly inhibit IAP [1]. </span>

S_22 1 S_27 1 S_31 1 S_15 1

<font face="Georgia" size="2">The pro-survival effects of Akt are expressed by Akt's inhibition of cas9 [1]. </font>

<font face="Georgia" size="2">Caspase 3 has a positive feedback effect on caspase 9 [1,2,3]. </font>

<font face="Georgia" size="2">IAP inhibits caspase 9 [1,2,3]. </font>

<font face="Georgia" size="2">Caspase 12 activates caspase 9 [1]. </font>

S_37 1 S_23 1 S_38 1 S_27 1 S_23 1 S_38 1

<font face="Georgia" size="2">Cas8 and JNK are activators of BID but both require the presence of p53 to activate BID. BclX is an inhibitor of BID and is dominant over all activators [1]. </font>

<span style="font-family: Georgia; font-size: small;">p53 activates BID [1,2,3]. </span>

<font face="Georgia" size="2">Cas8 activates BID [1,2,3]. </font>

<span style="font-family: Georgia; font-size: small;">JNK activates BID [1,2,3]. </span>

<font face="Georgia" size="2">BclX inhibits BID [1,2,3]. </font>

S_18 1 S_32 1 S_24 1 S_28 1 S_32 1 S_24 1

<font face="Georgia" size="2">TRADD activates FADD [1]. </font>

<font face="Georgia" size="2">TRADD activates FADD [1,2].</font>

S_13 1