Programmed cell death (PCD) is an essential cellular mechanism that is evolutionary conserved, mediated through various pathways and acts by integrating different stimuli. Many diseases such as neurodegenerative diseases and cancers are found to be caused by, or associated with, regulations in the cell death pathways. Yeast Saccharomyces cerevisiae, is a unicellular eukaryotic organism that shares with human cells components and pathways of the PCD and is therefore used as a model organism. Boolean modeling is becoming promising approach to capture qualitative behavior and describe essential properties of such complex networks. Here we present large literature-based and to our knowledge first Boolean model that combines pathways leading to apoptosis (a type of PCD) in yeast. Analysis of the yeast model confirmed experimental findings of anti-apoptotic role of Bir1p and pro-apoptotic role of Stm1p and revealed activation of the stress protein kinase Hog proposing the maximal level of activation upon heat stress. In addition we extended the yeast model and created an in silico humanized yeast in which human pro- and anti-apoptotic regulators Bcl-2 family and Valosin-contain protein (VCP) are included in the model. We showed that accumulation of Bax in silico humanized yeast shows apoptotic markers and that VCP is essential target of Akt Signaling. The presented Boolean model provides comprehensive description of yeast apoptosis network behavior. Extended model of humanized yeast gives new insights of how complex human disease like neurodegeneration can initially be tested. Helikar Tomas thelika@unmc.edu University of Nebraska - Lincoln 2013-06-04T15:10:00Z 2018-04-18T22:38:10Z

Hydroxide peroxide

 2018-04-14T20:56:06Z

Chemical input (external species)

 2018-04-14T20:35:54Z

Abnormal telomerase (external species)

 2015-11-15T17:58:35Z 2015-11-15T17:58:35Z 2015-11-15T17:58:35Z 2017-07-18T16:05:24Z

Mating pheromone (external species)

 2015-11-15T17:58:35Z

Copper ion

 2017-07-17T10:41:06Z 2015-11-15T17:58:35Z 2018-04-14T18:37:30Z 2017-07-18T16:05:24Z

Drug input (external species)

 2015-11-15T17:58:35Z 2015-11-15T17:58:35Z

Nuclear mediator of apoptosis in cytososl<div>UniProt AccessionID: P53920</div>

 2015-11-15T17:58:35Z

Separase protein<div>UniProt AccessionID: Q03018</div>

 2015-11-15T17:58:35Z

Reduced potassium dependency<div>UniProt AccessionID: P32561</div>

 2015-11-15T17:58:35Z

Mitosis entry checkpoint<div>UniProt AccessionID: P38111</div>

 2015-11-15T17:58:35Z

Syntaxin (SYN8)<div>UniProt AccessionID: Q00772</div>

 2017-07-18T16:05:24Z

Map kinase cascade<div>UniProt AccessionID: B3LT78</div>

 2015-11-15T17:58:35Z

<p style="orphans: 3; widows: 3; line-height: 1.5em; margin: 0.4em 0px 0.5em; color: rgb(79, 79, 79); font-family: Arial, sans-serif; font-size: 12px; background-color: rgb(255, 255, 255);"><span id="parentSpecies:viewSpeciesDescription">Sterile in nucleus</span></p><div style="font-size: 12px; color: rgb(79, 79, 79); font-family: Arial, sans-serif; line-height: 14.399999618530273px; background-color: rgb(255, 255, 255);">UniProt AccessionID: Q03497</div>

 2015-11-15T17:58:35Z

Mitochondrial Division<div>UniProt AccessionID: P47025</div>

 2015-11-15T17:58:35Z

Sterile in cytosol<div>UniProt AccessionID: Q03497</div>

 2015-11-15T17:58:35Z

<font face="Arial, Verdana" size="2">Porin</font><div><font face="Arial, Verdana" size="2">UniProt AccessionID: P04840, UniProt AccessionID: P40478</font></div>

 2018-04-14T21:00:49Z

<font size="2">Cell division Cycle</font><div><font size="2">UniProt AccessionID:&nbsp;P09119</font></div>

 2015-11-15T17:58:35Z

HOG1 dependent genes<div>UniProt AccessionID: P32485</div>

 2015-11-15T17:58:35Z

ER membrane protein complex<div>UniProt AccessionID: P53073</div>

 2015-11-15T17:58:35Z

Histon 2B<div>UniProt AccessionID:</div>

 2015-11-15T17:58:35Z

Mitochondria fragmentation

 2015-11-15T17:58:35Z

<font size="2" style="font-size: 10pt;">Cell division cycle</font><div><font size="2">UniProt AccessionID: P25694<br/></font><div style="font-size: 10pt;"><br/></div></div>

 2015-11-15T17:58:35Z

Superoxide dismutase<div>Uniprot AccessionID: P00445</div>

 2015-11-15T17:58:35Z

Translation machinery associated<div>UniProt AccessionID: P35691</div>

 2015-11-15T17:58:35Z

CytochromC in mitochondria<div>UniProt AccessionID: P07143</div>

 2015-11-15T17:58:35Z

Protein kinase A<div>UniProt ID:&nbsp;<a style="color: rgb(64, 148, 180); line-height: 20.08px; font-family: Verdana, Arial, sans-serif; font-size: 13.05px; text-decoration: none; border-bottom-width: 0px; cursor: pointer; background-color: rgb(255, 255, 255);" href="http://www.uniprot.org/uniprot/P12370">P12370</a></div><div>Gene Name:&nbsp;<a style="color: rgb(100, 42, 143); line-height: 17.99px; font-family: arial, helvetica, clean, sans-serif; font-size: 13px; white-space: nowrap; background-color: rgb(213, 222, 227);" href="http://www.ncbi.nlm.nih.gov/gene/34284" ref="ordinalpos=4&amp;ncbi_uid=34284&amp;link_uid=34284"><span class="highlight">Pka</span>-C1</a></div><div>Gene ID:&nbsp;<span style="color: rgb(87, 87, 87); line-height: 16.19px; font-family: arial, helvetica, clean, sans-serif; font-size: 11.69px; background-color: rgb(213, 222, 227);">34284</span></div><div><span style="color: rgb(87, 87, 87); line-height: 16.19px; font-family: arial, helvetica, clean, sans-serif; font-size: 11.69px; background-color: rgb(213, 222, 227);"></span>&nbsp;</div><div><span style="color: rgb(87, 87, 87); line-height: 16.19px; font-family: arial, helvetica, clean, sans-serif; font-size: 11.69px; background-color: rgb(213, 222, 227);"><table style="width: 723pt; border-collapse: collapse;" border="0" cellSpacing="0" cellPadding="0" width="964">\r\n <colgroup><col style="width: 723pt; mso-width-source: userset; mso-width-alt: 30848;" width="964">\r\n <tbody><tr style="height: 15pt;" height="20">\r\n\r\n <td style="border: 0px black; width: 723pt; height: 15pt; background-color: transparent;" class="xl65" height="20" width="964"><font color="#000000" size="3" face="Calibri">protein\r\n kinase, cAMP-dependent, catalytic, alpha</font></td>\r\n\r\n </tr>\r\n</tbody></table></span></div>

 2015-11-15T17:58:35Z

<p style="orphans: 3; widows: 3; line-height: 1.5em; margin: 0.4em 0px 0.5em; color: rgb(79, 79, 79); font-family: Arial, sans-serif; font-size: 12px; background-color: rgb(255, 255, 255);"><span id="parentSpecies:viewSpeciesDescription">Protein tyrosine phosphatase</span></p><div style="font-size: 12px; color: rgb(79, 79, 79); font-family: Arial, sans-serif; line-height: 14.399999618530273px; background-color: rgb(255, 255, 255);">UniProt AccessionID: P40048</div>

 2017-07-17T15:49:48Z

Dre2-TAH18 complex

 2015-11-15T17:58:35Z

Protosom complex

 2015-11-15T17:58:35Z

<font color="#575757" face="arial, helvetica, clean, sans-serif"><span style="font-size: 11.199999809265137px; line-height: 15.399999618530273px; white-space: nowrap;">Survival factor</span></font><div><font color="#575757" face="arial, helvetica, clean, sans-serif"><span style="font-size: 11.199999809265137px; line-height: 15.399999618530273px; white-space: nowrap;">UniProt AccessionID: Q05515</span></font></div>

 2015-11-15T17:58:35Z

CytochromC in cytososl<div>UniProt AccessionID:&nbsp;<a href="http://www.uniprot.org/uniprot/P08574" style="font-size: small; text-decoration: none; font-family: sans-serif; background-color: rgb(255, 255, 255);">P08574</a></div>

 2015-11-15T17:58:35Z

3' &gt;&gt; 5' exonuclease and endonuclease<div>UniProt AccessionID: P34220</div>

 2015-11-15T17:58:35Z

<font face="Arial, Verdana" size="2">Mitochondrial Fission</font><div><font face="Arial, Verdana" size="2">UniProt AccessionID: P40515</font></div>

 2015-11-15T17:58:35Z

Homologous to RAS proto-oncogene<div>UniProt AccessionID: P01120</div>

 2015-11-15T17:58:35Z

Mitotic chromosome determinant in mitochondria<div>UniProt AccessionID:&nbsp;</div>

 2015-11-15T17:58:35Z

<p style="orphans: 3; widows: 3; line-height: 1.5em; margin: 0.4em 0px 0.5em; color: rgb(79, 79, 79); font-family: Arial, sans-serif; font-size: 12px; background-color: rgb(255, 255, 255);"><span id="parentSpecies:viewSpeciesDescription">Nuclease 1 in nucleus</span></p><div style="font-size: 12px; color: rgb(79, 79, 79); font-family: Arial, sans-serif; line-height: 14.399999618530273px; background-color: rgb(255, 255, 255);">UniProt AccessionID: P08466</div>

 2015-11-15T17:58:35Z

Stress-inducible dual specificity phosphatase<div>UniProt AccessionID: P40479</div>

 2017-07-18T16:05:24Z

Destruction of cylinC/CDCk8

 2015-11-15T17:58:35Z

Cell death

 2018-04-14T18:58:54Z

Baculoviral IAP repeat-containing protein 1<div>UniProt AccessionID:&nbsp;</div>

 2018-04-14T20:56:06Z

HDA one similar<div>UniProt AccessionID: Q02959</div>

 2015-11-15T17:58:35Z

Reactive oxygen species in mitochondria

 2017-05-19T14:00:19Z

DNA fragmentation

 2018-04-14T20:58:36Z

Reactive oxygen species in cytososl

 2018-04-14T20:58:36Z

Apoptosis-inducing factor in mitochondria<div>UniProt AccessionID:&nbsp;<a href="http://www.uniprot.org/uniprot/P52923" style="text-decoration: none; font-family: sans-serif; font-size: small; background-color: rgb(255, 255, 255);">P52923</a></div>

 2015-11-15T17:58:35Z

Cyclic adenosine monophosphate<div>UniProt AccessionID:</div>

 2015-11-15T17:58:35Z

Multicopy suppressor of SNF1 mutation<div>UniProt AccessionID:&nbsp;</div>

 2015-11-15T17:58:35Z

Translation initiation factor (TIF3) in nucleus<div><p style="orphans: 3; widows: 3; line-height: 1.5em; margin: 0.4em 0px 0.5em; color: rgb(79, 79, 79); font-family: Arial, sans-serif; font-size: 12px; background-color: rgb(255, 255, 255);"><span style="line-height: 14.399999618530273px;">UniProt AccessionID: P39015</span></p></div>

 2015-11-15T17:58:35Z

Mitotic chromosome determinant in nucleus<div>UniProt AccessionID: Q12158</div>

 2015-11-15T17:58:35Z

Protein tyrosine phosphatase<div>UniProt AccessionID: P29461</div>

 2017-07-18T16:05:24Z

MetaCAspase<div>UniProt AccessionID: Q08601</div>

 2018-04-14T20:56:34Z

NADH dehydrogenase internal<div>UniProt AccessionID: P32340</div>

 2017-05-19T14:00:19Z

Suppressor of rho3<div>UniPro AccessionID: A6ZWS5</div>

 2015-11-15T17:58:35Z

KaryoPherin<div>UniProt AccessionID: P40069</div>

 2015-11-15T17:58:35Z

Translation initiation factor (TIF3) in cytososl<div><p style="orphans: 3; widows: 3; line-height: 1.5em; margin: 0.4em 0px 0.5em; color: rgb(79, 79, 79); font-family: Arial, sans-serif; font-size: 12px; background-color: rgb(255, 255, 255);"><span style="line-height: 14.399999618530273px;">UniProt AccessionID: P39015</span></p></div>

 2015-11-15T17:58:35Z

Resistance to lethality of MKK1P386 overexpression<div>UniProt AccessionID: A6ZWG2</div>

 2017-07-18T16:05:24Z

Lyase enzyme

 2015-11-15T17:58:35Z

Target of rapamycin<div>UniProt AccessionID: P35169</div>

 2015-11-15T17:58:35Z

High osmolarity glycerol response<div>UniProt AccessionID: Q03213</div>

 2017-07-17T15:49:48Z

SNZ proximal open reading frame<div>UniProt AccessionID: Q03144</div>

 2018-04-14T20:56:06Z

Nuclear mediator of apoptosis in nucleus<div><span style="color: rgb(79, 79, 79); font-family: Arial, sans-serif; font-size: 12px; line-height: 14.399999618530273px; background-color: rgb(255, 255, 255);">UniProt AccessionID: P53920</span></div>

 2015-11-15T17:58:35Z

Function required for yeast viability<div>UniProt AccessionID: P40492</div>

 2018-04-14T20:56:06Z

Nuclease 1 in mitochondria<div>UniProt AccessionID: P08466</div>

 2015-11-15T17:58:35Z

Apoptosis-inducing factor in nucleus<div>UniProt AccessionID:&nbsp;<a href="http://www.uniprot.org/uniprot/P52923" style="text-decoration: none; font-family: sans-serif; font-size: small; background-color: rgb(255, 255, 255);">P52923</a></div>

 2015-11-15T17:58:35Z

Mitochondria alteration

 2015-11-15T17:58:35Z

<p style="orphans: 3; widows: 3; line-height: 1.5em; margin: 0.4em 0px 0.5em; color: rgb(79, 79, 79); font-family: Arial, sans-serif; font-size: 12px; background-color: rgb(255, 255, 255);"><span id="parentSpecies:viewSpeciesDescription">Superoxide dismutase</span></p><div style="font-size: 12px; color: rgb(79, 79, 79); font-family: Arial, sans-serif; line-height: 14.399999618530273px; background-color: rgb(255, 255, 255);">Uniprot AccessionID: P00447</div>

 2017-05-19T14:00:19Z

*Heat positively regulates NMA111-CYT

*Heat positively regulates NMA111-CYT {[1][2]}

 S_59 1

*H2O2 positively regulates ESP1

*H2O2 positively regulates ESP1 {[1][2]}

 S_10 1

*Stress positively regulates RPD3

*Stress positively regulates RPD3 {[1][2]}

 S_36 1

*<span style="font-family: Arial, sans-serif; font-size: 12px; line-height: 20px; text-align: center; background-color: rgb(255, 255, 255);">Abnormal Telomerase positively regulates MEC1</span>

*<span style="font-family: Arial, sans-serif; font-size: 12px; line-height: 20px; text-align: center; background-color: rgb(255, 255, 255);">Abnormal Telomerase positively regulates MEC1 {[1][2]}</span>

 S_20 1

SLT2 &nbsp;protein is independently activated by Heat [1,2] and RLM1 [1,2]. PTP2, SDP1, and Stress all individually inhibit activation of SLT2 protein [1,2]

PTP2, SDP1, and Stress are listed as positive regulators with certain conditions in order to get equivalent behavior to the original expression SLT2 =(!PTP2) OR (!SDP1) OR (!Stress) OR (Heat) OR (RLM1).

<span style="font-family: Arial, sans-serif; font-size: 12px; line-height: 24px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">*SDP1 negatively regulates SLT2 {[1][2]}</span>

*PTP2 negatively regulates SLT2 {[1][2]}

<span style="font-family: Arial, sans-serif; font-size: 12px; line-height: 24px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">*Heat positively regulates SLT2 {[1][2]}</span>

<span style="font-family: Arial, sans-serif; font-size: 12px; line-height: 24px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">*Stress negatively regulates SLT2 {[1][2]}</span>

<span style="font-size: 10pt;">*RLM1 forms a feedback loop to trigger activation of SLT2 and PTP2 {[1]-p.4}</span>

 S_37 1 S_52 1 S_36 1 S_59 1 S_52 1 S_37 1 S_36 1 S_36 1 S_52 1 S_37 1 S_61 1 S_37 1 S_52 1 S_59 1 S_36 1 S_61 1

*Mating pheromone positively regulates MAPK

*Mating pheromone positively regulates MAPK {[1][2]}

 S_48 1

*STE20-CYT positively regulates STE20-NUC

*STE20-CYT positively regulates STE20-NUC {[1][2]}

 S_9 1

<span style="LINE-HEIGHT: 24px; WIDOWS: 3; BACKGROUND-COLOR: rgb(255,255,255); FONT-FAMILY: Arial, sans-serif; ORPHANS: 3; FONT-SIZE: 12px">*Housekeeping positively regulates MDV1</span>

<span style="LINE-HEIGHT: 24px; WIDOWS: 3; BACKGROUND-COLOR: rgb(255,255,255); FONT-FAMILY: Arial, sans-serif; ORPHANS: 3; FONT-SIZE: 12px">*Housekeeping positively regulates MDV1 {[1]}</span>

 S_32 1

*MAPK positively regulates STE20-CYT

*MAPK positively regulates STE20-CYT {[1][2]}

 S_6 1

<span style="LINE-HEIGHT: 24px; WIDOWS: 3; BACKGROUND-COLOR: rgb(255,255,255); FONT-FAMILY: Arial, sans-serif; ORPHANS: 3; FONT-SIZE: 12px">*Housekeeping positively regulates POR1-2</span>

<span style="LINE-HEIGHT: 24px; WIDOWS: 3; BACKGROUND-COLOR: rgb(255,255,255); FONT-FAMILY: Arial, sans-serif; ORPHANS: 3; FONT-SIZE: 12px">*Housekeeping positively regulates POR1-2 {[1]}</span>

 S_32 1

*Adozelesin positively regulates CDC6

*Adozelesin positively regulates CDC6 {[1][2]}

 S_63 1

*HOG1 positively regulates HOG1-Dep

*HOG1 positively regulates HOG1-Dep {[1][2]}

 S_65 1

<span style="color: rgb(79, 79, 79); font-family: Arial, sans-serif; font-size: 12px; line-height: 24px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">*Housekeeping positively regulates EMC4</span>

<span style="color: rgb(79, 79, 79); font-family: Arial, sans-serif; font-size: 12px; line-height: 24px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">*Housekeeping positively regulates EMC4 {[1]}</span>

 S_32 1

*AIF1-NUC positively regulates H2B

*HOS3 positively regulates H2B

<span style="font-family: Arial, sans-serif; font-size: 12px; line-height: 24px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">*NUC1-NUC positively regulates H2B</span>

<span style="font-family: Arial, sans-serif; font-size: 12px; line-height: 24px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">*RPD3 positively regulates H2B </span>

<span style="font-family: Arial, sans-serif; font-size: 12px; line-height: 24px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">*STE20-NUC positively regulates H2B</span>

<span style="font-family: Arial, sans-serif; font-size: 12px; line-height: 24px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">*RPD3 positively regulates H2B {[1][6]}</span>

*AIF1-NUC positively regulates H2B {[1][2]}

<span style="font-family: Arial, sans-serif; font-size: 12px; line-height: 24px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">*NUC1-NUC positively regulates H2B {[1][5]}</span>

*HOS3 positively regulates H2B {[1][4]}

<span style="font-family: Arial, sans-serif; font-size: 12px; line-height: 24px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">*STE20-NUC positively regulates H2B {[1][3]}</span>

 S_41 1 S_7 1 S_71 1 S_3 1 S_35 1

<span style="font-family: Arial, sans-serif; font-size: 12px; line-height: 24px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">*FIS1 negatively regulates MT-Frag</span>

*DRE2_TAH18 negatively regulates MT-Frag

*MT-ALT positively regulates MT-Frag

*H2O2 positively regulates MT-Frag

*MDV1 positively regulates MT-Frag

*H2O2 positively regulates MT-Frag {[1][3]}

*MT-ALT positively regulates MT-Frag {[1]}

*DRE2_TAH18 negatively regulates MT-Frag {[1][3]}

<span style="font-family: Arial, sans-serif; font-size: 12px; line-height: 24px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">*FIS1 negatively regulates MT-Frag {[1][2]}</span>

*MDV1 positively regulates MT-Frag {[1][2]}

 S_10 1 S_25 1 S_8 1 S_30 1 S_72 1

<span style="LINE-HEIGHT: 24px; WIDOWS: 3; BACKGROUND-COLOR: rgb(255,255,255); FONT-FAMILY: Arial, sans-serif; ORPHANS: 3; FONT-SIZE: 12px">*Housekeeping positively regulates CDC48</span>

<span style="LINE-HEIGHT: 24px; WIDOWS: 3; BACKGROUND-COLOR: rgb(255,255,255); FONT-FAMILY: Arial, sans-serif; ORPHANS: 3; FONT-SIZE: 12px">*Housekeeping positively regulates CDC48 {[1]}</span>

 S_32 1

*Heat positively regulates SOD1

*Heat positively regulates SOD1 {[1]}

 S_59 1

<span style="LINE-HEIGHT: 24px; WIDOWS: 3; BACKGROUND-COLOR: rgb(255,255,255); FONT-FAMILY: Arial, sans-serif; ORPHANS: 3; FONT-SIZE: 12px">*Housekeeping positively regulates MMI1 </span>

<span style="LINE-HEIGHT: 24px; WIDOWS: 3; BACKGROUND-COLOR: rgb(255,255,255); FONT-FAMILY: Arial, sans-serif; ORPHANS: 3; FONT-SIZE: 12px">*Housekeeping positively regulates MMI1 {[1]}</span>

 S_32 1

*Acetic Acid positively regulates CytC-MT

*MCD1-MT positively regulates CytC-MT

*MCD1-MT positively regulates CytC-MT {[1] [3]}

*Acetic Acid positively regulates CytC-MT {[1][2]}

 S_14 1 S_33 1

Heat and RAS2 both independently positively regulate PKA [1,2,3].

*RAS2 positively regulates PKA {[1][2]}

<div><span style="font-size: 10pt;">*Heat positively regulates PKA {[1][3]}</span></div>

 S_31 1 S_59 1

*HOG1-Dep positively regulates PTP3

*HOG1-Dep positively regulates PTP3 {[1][2]}

 S_13 1

<span style="color: rgb(79, 79, 79); font-family: Arial, sans-serif; font-size: 12px; line-height: 18px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">*Housekeeping positively regulates DRE2_TAH18</span>

<span style="color: rgb(79, 79, 79); font-family: Arial, sans-serif; font-size: 12px; line-height: 18px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">*Housekeeping positively regulates DRE2_TAH18 {[1]}</span>

 S_32 1

*CDC6 positively regulates Protosom complex

*CDC6 positively regulates Protosom complex {[1][2]}

 S_12 1

<span style="font-family: Arial, sans-serif; font-size: 12px; line-height: 24px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">*Housekeeping positively regulates SVF1</span>

<span style="font-family: Arial, sans-serif; font-size: 12px; line-height: 24px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">*Housekeeping positively regulates SVF1 {[1]}</span>

 S_32 1

*CDC48 positively regulates CytC-CYT

CytC-MT positively regulates CytC-CYT

*CDC48 positively regulates CytC-CYT {[1] [2]}

CytC-MT positively regulates CytC-CYT {[1] [2]}

 S_22 1 S_18 1

*MG2 positively regulates Tat-D

*MG2 positively regulates Tat-D {[1][2]}

 S_34 1

*Housekeeping positively regulates FIS1

*Housekeeping positively regulates FIS1 {[1]}

 S_32 1

*RedActinDyn positively regulates RAS2

<span style="font-family: Arial, sans-serif; font-size: 12px; line-height: 24px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">*TOR1 positively regulates RAS2 </span>

<span style="font-family: Arial, sans-serif; font-size: 12px; line-height: 24px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">*TOR1 positively regulates RAS2 {[1][3]}</span>

*RedActinDyn positively regulates RAS2 {[1][2]}

 S_53 1 S_64 1

<span style="LINE-HEIGHT: 24px; WIDOWS: 3; BACKGROUND-COLOR: rgb(255,255,255); FONT-FAMILY: Arial, sans-serif; ORPHANS: 3; FONT-SIZE: 12px">*Housekeeping positively regulates MCD1-MT</span>

<span style="LINE-HEIGHT: 24px; WIDOWS: 3; BACKGROUND-COLOR: rgb(255,255,255); FONT-FAMILY: Arial, sans-serif; ORPHANS: 3; FONT-SIZE: 12px">*Housekeeping positively regulates MCD1-MT {[1]}</span>

 S_32 1

*KAP123 positively regulates NUC1-NUC

*KAP123 positively regulates NUC1-NUC {[1][2]}

 S_57 1

*MSN2-4 positively regulates SDP1

*MSN2-4 positively regulates SDP1 {[1][2]}

 S_47 1

*SLT2 negatively regulates DesCyclinCCDK8

*SLT2 negatively regulates DesCyclinCCDK8 {[1][2]}

 S_5 1

<span style="color: rgb(79, 79, 79); font-family: Arial, sans-serif; font-size: 12px; line-height: 18px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">DNA-Frag positively regulates Apoptosis [1,4].&nbsp;</span><span style="color: rgb(79, 79, 79); font-family: Arial, sans-serif; font-size: 12px; line-height: 18px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">ROS-CYT positively regulates Apoptosis [1,5].&nbsp;</span><span style="color: rgb(79, 79, 79); font-family: Arial, sans-serif; font-size: 12px; line-height: 18px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">CU2 and CPR3 in conjunction positively regulate Apoptosis [1,3].</span><span style="color: rgb(79, 79, 79); font-family: Arial, sans-serif; font-size: 12px; line-height: 18px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">&nbsp;</span><span style="color: rgb(79, 79, 79); font-family: Arial, sans-serif; font-size: 12px; line-height: 18px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">AceticAcid or H202 and not POR1-2 activate Apoptosis [1,6]. YCA1 and not&nbsp;</span><span style="color: rgb(79, 79, 79); font-family: Arial, sans-serif; font-size: 12px; line-height: 18px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">BIR1 regulate Apoptosis [1,7].</span><span style="color: rgb(79, 79, 79); font-family: Arial, sans-serif; font-size: 12px; line-height: 18px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">&nbsp;</span><span style="color: rgb(79, 79, 79); font-family: Arial, sans-serif; font-size: 12px; line-height: 18px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">FVY10 negatively regulates Apoptosis [1,2].&nbsp;</span><span style="color: rgb(79, 79, 79); font-family: Arial, sans-serif; font-size: 12px; line-height: 18px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">&nbsp;</span><span style="color: rgb(79, 79, 79); font-family: Arial, sans-serif; font-size: 12px; line-height: 18px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">&nbsp;</span><span style="color: rgb(79, 79, 79); font-family: Arial, sans-serif; font-size: 12px; line-height: 18px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">SNO1 negatively regulates Apoptosis [1,2].</span>

*FVY10 negatively regulates Apoptosis {[1] [2]}

*POR1-2 negatively regulates Apoptosis in the presence of H202 {[1][6]}

*CU2 works in conjunction with CPR3 to positively regulate Apoptosis {[1][[3]}

*Overexpression of BIR1 reduces Apoptosis {[1][7]}

<span style="color: rgb(79, 79, 79); font-family: Arial, sans-serif; font-size: 12px; line-height: 18px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">*POR1-2 negatively regulates Apoptosis in the presence of AceticAcid {[1][6]}</span><div>*POR1-2 negatively regulates Apoptosis in the presence of H202 {[1][6]}</div>

*ROS-CYT positively regulates Apoptosis {[1][5]}

*SNO1 negatively regulates Apoptosis {[1][2]}

*CU2 works in conjunction with CPR3 to positively regulate Apoptosis {[1][[3]}

*Acetic Acid acts as an indirect inducer of Apoptosis {[1][6][7]}

*Apoptosis is Y-cal1p dependent {[1][7][8][9]}

*DNA-Frag positively regulates Apoptosis {[1][4]}

 S_11 1 S_69 1 S_10 1 S_40 1 S_14 1 S_67 1 S_43 1 S_69 1 S_10 1 S_11 1 S_40 1 S_14 1 S_69 1 S_10 1 S_11 1 S_40 1 S_67 1 S_14 1 S_58 1 S_69 1 S_10 1 S_11 1 S_40 1 S_14 1 S_67 1 S_54 1 S_69 1 S_10 1 S_11 1 S_40 1 S_67 1 S_14 1 S_40 1 S_69 1 S_67 1 S_67 1 S_69 1 S_10 1 S_11 1 S_44 1 S_43 1 S_10 1 S_11 1 S_40 1 S_14 1 S_69 1 S_40 1 S_69 1 S_10 1 S_11 1 S_67 1 S_14 1 S_14 1 S_69 1 S_10 1 S_11 1 S_40 1 S_67 1 S_69 1 S_40 1 S_67 1 S_10 1 S_11 1 S_69 1 S_67 1 S_10 1 S_11 1 S_40 1 S_44 1 S_54 1 S_43 1 S_10 1 S_11 1 S_40 1 S_69 1 S_67 1 S_51 1 S_58 1 S_10 1 S_11 1 S_40 1 S_14 1 S_69 1 S_67 1 S_69 1 S_10 1 S_11 1 S_40 1 S_14 1 S_67 1 S_44 1 S_69 1 S_10 1 S_11 1 S_40 1 S_67 1 S_14 1 S_10 1 S_11 1 S_40 1 S_14 1 S_10 1 S_69 1 S_11 1 S_40 1 S_14 1 S_67 1 S_69 1 S_10 1 S_58 1 S_40 1 S_11 1 S_44 1 S_67 1 S_51 1 S_14 1 S_54 1 S_43 1

<span style="color: rgb(79, 79, 79); font-family: Arial, sans-serif; font-size: 12px; line-height: 18px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">*</span><span style="color: rgb(79, 79, 79); font-family: Arial, sans-serif; font-size: 12px; orphans: 3; widows: 3; line-height: 20px; text-align: center; background-color: rgb(255, 255, 255);">NMA111-NUC negatively regulates BIR1 [1,2]</span>

*<span style="font-family: Arial, sans-serif; font-size: 12px; line-height: 20px; text-align: center; background-color: rgb(255, 255, 255);">NMA111-NUC inactivates BIR1 {[1][2]}</span>

 S_68 1

*H2O2 positively regulates HOS3

*H2O2 positively regulates HOS3 {[1][2]}

 S_10 1

NDI1 positively regulates ROS-MT in the absence of SOD2

NDI1 positively regulates ROS-MT in the absence of SOD2

NDI1 positively regulates ROS-MT in the absence of SOD2 {[1] [2]}

NDI1 positively regulates ROS-MT in the absence of SOD2 {[1] [2]}

 S_55 1 S_73 1

Tat-D activates DNA-frag [1,2]. STM1-NUC deactivates DNA-Fra [1,3].

*STM1-NUC negatively regulates DNA-Frag {[1][3]}

*Tat-D positively regulates DNA-Frag {[1][2]}

 S_29 1 S_49 1 S_29 1

<span style="color: rgb(79, 79, 79); font-family: Arial, sans-serif; font-size: 12px; line-height: 24px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">CDC48 , DesCyclinCCDK8 [3], ESP1 [6], RAS2 [2], and NDI1 independently positively regulate ROS-CYT [1].&nbsp;</span>ROS-CYT is negatively regulated by SVF1 in the&nbsp;<span style="color: rgb(79, 79, 79); font-family: Arial, sans-serif; font-size: 12px; line-height: 24px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">presence of H2O2 or Acetic Acid [1,7]. ROS-CYT is negatively regulated by EMC4 when in the presence of H2O2 [1,4].</span>

<span style="font-family: Arial, sans-serif; font-size: 12px; line-height: 24px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">*EMC4 negatively regulates ROS-CYT in the presence of H2O2 {[1][4]}</span><div>*SVF1 negatively regulates ROS-CYT&nbsp;<span style="font-family: Arial, sans-serif; font-size: 12px; line-height: 24px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">in the presence of H2O2 or Acetic Acid {[1][7]}</span></div>

<span style="font-family: Arial, sans-serif; font-size: 12px; line-height: 24px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">*DesCyclinCCDK8</span><span style="font-family: Arial, sans-serif; font-size: 12px; line-height: 24px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">&nbsp;positively regulates ROS-CYT {[1][3]}</span>

<span style="font-family: Arial, sans-serif; font-size: 12px; line-height: 24px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">*RAS2 positively regulates ROS-CYT {[1] [2]}</span>

<span style="font-family: Arial, sans-serif; font-size: 12px; line-height: 24px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">*Salt positively regulates ROS-CYT {[1][5]}</span>

*Two occurrences of CDC48 positively regulates ROS-CYT {[1]}

*Two occurrences of NDI1 positively regulates ROS-CYT {[1]}

*SVF1 negatively regulates ROS-CYT&nbsp;<span style="font-family: Arial, sans-serif; font-size: 12px; line-height: 24px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">in the presence of H2O2 or Acetic Acid {[1][7]}</span>

<span style="font-family: Arial, sans-serif; font-size: 12px; line-height: 24px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">*RedActinDyn positively regulates ROS-CYT {[1] [8]}</span>

<span style="font-family: Arial, sans-serif; font-size: 12px; line-height: 24px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">*SOD2 positively regulates ROS-CYT {[1][8]}</span>

*EMC4 negatively regulates ROS-CYT in the presence of H2O2 {[1][4]}

<span style="font-family: Arial, sans-serif; font-size: 12px; line-height: 24px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">*ESP1 positively regulates ROS-CYT {[1] [6]}</span>

*SVF1 negatively regulates ROS-CYT&nbsp;<span style="font-family: Arial, sans-serif; font-size: 12px; line-height: 24px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">in the presence of H2O2 or Acetic Acid {[1][7]}</span>

 S_31 1 S_55 1 S_66 1 S_2 1 S_10 1 S_15 1 S_53 1 S_38 1 S_10 1 S_27 1 S_14 1 S_27 1 S_19 1 S_18 1

<span style="color: rgb(79, 79, 79); font-family: Arial, sans-serif; font-size: 12px; line-height: 18px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">*Housekeeping positively regulates AIF1-MT</span>

<span style="color: rgb(79, 79, 79); font-family: Arial, sans-serif; font-size: 12px; line-height: 18px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">*Housekeeping positively regulates AIF1-MT {[1]}</span>

 S_32 1

*AdenylateCyclase positively regulates cAMP

*TOR1 positively regulates cAMP

*TOR1 positively regulates cAMP {[1][2]}

*AdenylateCyclase positively regulates cAMP {[1][2]}

 S_64 1 S_62 1

PKA positively regulates MSN2-4.

*When heat shock inhibits activity to PKA, the inhibition effect PKA has on MSN2-4 is released.<span style="font-size: 10pt;">{[1]-p.5, [2]}</span>

 S_23 1

*Protosom negatively regulates STM1-NUC in the presence of STM1-CYT

*Protosom negatively regulates STM1-NUC in the presence of STM1-CYT {[1][2]}

*Protosom negatively regulates STM1-NUC in the presence of STM1-CYT {[1][2]}

 S_60 1 S_26 1

*ESP1 positively regulates MDC1-NUC

*ESP1 positively regulates MDC1-NUC {[1][2]}

 S_2 1

The PTP2 protein is positively regulated by RLM1 [1,2].

<span style="font-size: 10pt;">*RLM1 forms a feedback loop to trigger activation of SLT2 and PTP2 {[1]-p.4}</span>

 S_61 1

<span style="LINE-HEIGHT: 24px; WIDOWS: 3; BACKGROUND-COLOR: rgb(255,255,255); FONT-FAMILY: Arial, sans-serif; ORPHANS: 3; FONT-SIZE: 12px">*CytC-CYT positively regulates YCA1</span>

*SRO7 negatively regulates YCA1 in the presence of Salt {[1] [4]}

<span style="LINE-HEIGHT: 24px; WIDOWS: 3; BACKGROUND-COLOR: rgb(255,255,255); FONT-FAMILY: Arial, sans-serif; ORPHANS: 3; FONT-SIZE: 12px">*MT-Frag positively regulates YCA1 {[1] [6]}</span>

*SRO7 negatively regulates YCA1 in the presence of Salt {[1] [4]}

<span style="LINE-HEIGHT: 24px; WIDOWS: 3; BACKGROUND-COLOR: rgb(255,255,255); FONT-FAMILY: Arial, sans-serif; ORPHANS: 3; FONT-SIZE: 12px">*RedActinDyn positively regulates YCA1 {[1] [2]}</span>

*ROS-CYT positively regulates YCA1 {[1] [2]}

<span style="LINE-HEIGHT: 24px; WIDOWS: 3; BACKGROUND-COLOR: rgb(255,255,255); FONT-FAMILY: Arial, sans-serif; ORPHANS: 3; FONT-SIZE: 12px">*CytC-CYT positively regulates YCA1 {[1] [6]}</span>

<span style="LINE-HEIGHT: 24px; WIDOWS: 3; BACKGROUND-COLOR: rgb(255,255,255); FONT-FAMILY: Arial, sans-serif; ORPHANS: 3; FONT-SIZE: 12px">*MEC1 positively regulates YCA1 {[1] [3]}</span>

 S_44 1 S_4 1 S_28 1 S_53 1 S_66 1 S_56 1 S_17 1

<span style="LINE-HEIGHT: 24px; WIDOWS: 3; BACKGROUND-COLOR: rgb(255,255,255); FONT-FAMILY: Arial, sans-serif; ORPHANS: 3; FONT-SIZE: 12px">*Housekeeping positively regulates NDI1</span>

<span style="LINE-HEIGHT: 24px; WIDOWS: 3; BACKGROUND-COLOR: rgb(255,255,255); FONT-FAMILY: Arial, sans-serif; ORPHANS: 3; FONT-SIZE: 12px">*Housekeeping positively regulates NDI1 {[1]}</span>

 S_32 1

<span style="LINE-HEIGHT: 24px; WIDOWS: 3; BACKGROUND-COLOR: rgb(255,255,255); FONT-FAMILY: Arial, sans-serif; ORPHANS: 3; FONT-SIZE: 12px">*Housekeeping positively regulates SRO7</span>

<span style="LINE-HEIGHT: 24px; WIDOWS: 3; BACKGROUND-COLOR: rgb(255,255,255); FONT-FAMILY: Arial, sans-serif; ORPHANS: 3; FONT-SIZE: 12px">*Housekeeping positively regulates SRO7 {[1]}</span>

 S_32 1

*NUC1-MT positively regulates KAP123

*NUC1-MT positively regulates KAP123 {[1][2]}

 S_70 1

<span style="LINE-HEIGHT: 24px; WIDOWS: 3; BACKGROUND-COLOR: rgb(255,255,255); FONT-FAMILY: Arial, sans-serif; ORPHANS: 3; FONT-SIZE: 12px">*Housekeeping positively regulates STM1-CYT</span>

<span style="LINE-HEIGHT: 24px; WIDOWS: 3; BACKGROUND-COLOR: rgb(255,255,255); FONT-FAMILY: Arial, sans-serif; ORPHANS: 3; FONT-SIZE: 12px">*Housekeeping positively regulates STM1-CYT {[1]}</span>

 S_32 1

HOG1 and SLT2 independently activate RLM1 [1,2]

*HOG1 positively regulates RLM1 {[1][2]}

<span style="font-family: Arial, sans-serif; font-size: 12px; line-height: 24px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">*SLT2 positively regulates RLM1 {[1][2]}</span>

 S_5 1 S_65 1

<span style="color: rgb(79, 79, 79); font-family: Arial, sans-serif; font-size: 12px; line-height: 18px; orphans: 3; widows: 3;">*RAS2 positively regulates Adenylate Cyclase</span>

<span style="color: rgb(79, 79, 79); font-family: Arial, sans-serif; font-size: 12px; line-height: 24px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">*Stress negatively regulates Adenylate Cyclase</span>

<span style="color: rgb(79, 79, 79); font-family: Arial, sans-serif; font-size: 12px; line-height: 18px; orphans: 3; widows: 3;">*RAS2 positively regulates Adenylate Cyclase {[2][3]}</span>

<span style="color: rgb(79, 79, 79); font-family: Arial, sans-serif; font-size: 12px; line-height: 24px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">*Stress negatively regulates Adenylate Cyclase {[1][3]}</span>

 S_31 1 S_36 1

*Stress positively regulates TOR1

*Stress positively regulates TOR1 {[1][2]}

 S_36 1

*<span style="font-family: Arial, sans-serif; font-size: 12px; line-height: 24px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">PTP2 negatively regulates HOG1</span>

*PTP3 negatively regulates HOG1

*Stress positively regulates HOG1

*<span style="font-family: Arial, sans-serif; font-size: 12px; line-height: 24px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">PTP2 negatively regulates HOG1 {[1][2]}</span>

*PTP3 negatively regulates HOG1 {[1][2]}

*Stress positively regulates HOG1 {[1][2]}

 S_24 1 S_52 1 S_36 1 S_52 1 S_24 1 S_52 1 S_24 1 S_36 1

<span style="LINE-HEIGHT: 24px; WIDOWS: 3; BACKGROUND-COLOR: rgb(255,255,255); FONT-FAMILY: Arial, sans-serif; ORPHANS: 3; FONT-SIZE: 12px">*Housekeeping positively regulates SNO1</span>

<span style="LINE-HEIGHT: 24px; WIDOWS: 3; BACKGROUND-COLOR: rgb(255,255,255); FONT-FAMILY: Arial, sans-serif; ORPHANS: 3; FONT-SIZE: 12px">*Housekeeping positively regulates SNO1 {[1]}</span>

 S_32 1

<span style="color: rgb(79, 79, 79); font-family: Arial, sans-serif; font-size: 12px; line-height: 18px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">*NMA111-CYT positively regulates NMA111-NUC</span>

<span style="color: rgb(79, 79, 79); font-family: Arial, sans-serif; font-size: 12px; line-height: 18px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">*NMA111-CYT positively regulates NMA111-NUC {[1][2]}</span>

 S_1 1

*Housekeeping positively regulates FVY10

*Housekeeping positively regulates FVY10 {[1]}

 S_32 1

*H2O2 positively regulates NUC1-MT

*H2O2 positively regulates NUC1-MT {[1][2]}

 S_10 1

*AIF1-MT positively regulates AIF1-NUC

*AIF1-MT positively regulates AIF1-NUC {[1][2]}

 S_45 1

*MMI1 positively regulates MT-ALT

<span style="LINE-HEIGHT: 24px; WIDOWS: 3; BACKGROUND-COLOR: rgb(255,255,255); FONT-FAMILY: Arial, sans-serif; ORPHANS: 3; FONT-SIZE: 12px">*MT-Frag positively regulates MT-ALT</span>

<span style="LINE-HEIGHT: 24px; WIDOWS: 3; BACKGROUND-COLOR: rgb(255,255,255); FONT-FAMILY: Arial, sans-serif; ORPHANS: 3; FONT-SIZE: 12px">*PKA positively regulates MT-ALT</span>

<span style="LINE-HEIGHT: 24px; WIDOWS: 3; BACKGROUND-COLOR: rgb(255,255,255); FONT-FAMILY: Arial, sans-serif; ORPHANS: 3; FONT-SIZE: 12px">*RAS2 positively regulates MT-ALT</span>

<span style="LINE-HEIGHT: 24px; WIDOWS: 3; BACKGROUND-COLOR: rgb(255,255,255); FONT-FAMILY: Arial, sans-serif; ORPHANS: 3; FONT-SIZE: 12px">*MT-Frag positively regulates MT-ALT {[1][2]}</span>

<span style="LINE-HEIGHT: 24px; WIDOWS: 3; BACKGROUND-COLOR: rgb(255,255,255); FONT-FAMILY: Arial, sans-serif; ORPHANS: 3; FONT-SIZE: 12px">*PKA positively regulates MT-ALT {[1] [3]}</span>

<span style="LINE-HEIGHT: 24px; WIDOWS: 3; BACKGROUND-COLOR: rgb(255,255,255); FONT-FAMILY: Arial, sans-serif; ORPHANS: 3; FONT-SIZE: 12px">*RAS2 positively regulates MT-ALT {[1] [4]}</span>

*MMI1 positively regulates MT-ALT {[1] [4]}

 S_21 1 S_17 1 S_31 1 S_23 1

<span style="LINE-HEIGHT: 24px; WIDOWS: 3; BACKGROUND-COLOR: rgb(255,255,255); FONT-FAMILY: Arial, sans-serif; ORPHANS: 3; FONT-SIZE: 12px">*Housekeeping positively regulates SOD2</span>

<span style="LINE-HEIGHT: 24px; WIDOWS: 3; BACKGROUND-COLOR: rgb(255,255,255); FONT-FAMILY: Arial, sans-serif; ORPHANS: 3; FONT-SIZE: 12px">*Housekeeping positively regulates SOD2 {[1]}</span>

 S_32 1