BioPAX pathway converted from "DNA Damage/Telomere Stress Induced Senescence" in the Reactome database.DNA Damage/Telomere Stress Induced SenescenceThis event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a>LEFT-TO-RIGHTInactivation of Cyclin A:Cdk2 complexes by p27/p21This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a>CCNA:CDK2Reactome DB_ID: 10423040nucleoplasmGENE ONTOLOGYGO:0005654Converted from EntitySet in ReactomeCCNACyclin AReactome DB_ID: 10413426CCNA1F1P4N0Reactome DB_ID: 10413420UniProt:F1P4N0Gallus gallusNCBI Taxonomy9031UniProtF1P4N01EQUAL465EQUALReactome Database ID Release 7510413420Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10413420ReactomeR-GGA-688911Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-GGA-68891.1Reactomehttp://www.reactome.orgCCNA2CCNA2F1NJI2Reactome DB_ID: 10413424UniProt:F1NJI2CCNA2UniProtF1NJI21EQUAL432EQUALReactome Database ID Release 7510413424Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10413424ReactomeR-GGA-689051Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-GGA-68905.1Reactome Database ID Release 7510413426Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10413426ReactomeR-GGA-752021Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-GGA-75202.11CDK2CDK2A2IAR9Reactome DB_ID: 10413369UniProt:A2IAR9CDK2UniProtA2IAR91EQUAL298EQUALReactome Database ID Release 7510413369Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10413369ReactomeR-GGA-683651Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-GGA-68365.11Reactome Database ID Release 7510423040Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10423040ReactomeR-GGA-1416081Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-GGA-141608.1Converted from EntitySet in Reactomep21,p27CDKN1A,CDKN1BReactome DB_ID: 10424182CDKN1ACDKN1AA0A3Q2UBS2Reactome DB_ID: 10424180UniProt:A0A3Q2UBS2CDKN1AUniProtA0A3Q2UBS22EQUAL164EQUALReactome Database ID Release 7510424180Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10424180ReactomeR-GGA-1825851Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-GGA-182585.1CDKN1BCDKN1BQ8JIV2Reactome DB_ID: 10424174UniProt:Q8JIV2CDKN1BUniProtQ8JIV21EQUAL198EQUALReactome Database ID Release 7510424174Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10424174ReactomeR-GGA-1825631Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-GGA-182563.1Reactome Database ID Release 7510424182Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10424182ReactomeR-GGA-1825581Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-GGA-182558.1Cyclin A:Cdk2:p21/p27 complexReactome DB_ID: 1042425011Reactome Database ID Release 7510424250Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10424250ReactomeR-GGA-1879261Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-GGA-187926.1ACTIVATIONGENE ONTOLOGYGO:0004861gene ontology term for cellular functionMIMI:0355Same Catalyst ActivityReactome Database ID Release 7510424256Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10424256Reactome Database ID Release 7510424258Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10424258ReactomeR-GGA-1879341Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-GGA-187934.1During G1, the activity of cyclin-dependent kinases (CDKs) is controlled by the CDK inhibitors (CKIs) CDKN1A (p21) and CDKN1B (p27), thereby preventing premature entry into S phase (Guardavaccaro and Pagano, 2006). 10323868Pubmed1999Ubiquitination of p27 is regulated by Cdk-dependent phosphorylation and trimeric complex formationMontagnoli, AFiore, FEytan, ECarrano, ACDraetta, GFHershko, APagano, MicheleGenes Dev 13:1181-98242751Pubmed1993The p21 Cdk-interacting protein Cip1 is a potent inhibitor of G1 cyclin-dependent kinases.Harper, JWAdami, GRWei, NKeyomarsi, KElledge, SJCell 75:805-167624798Pubmed1995Role of the ubiquitin-proteasome pathway in regulating abundance of the cyclin-dependent kinase inhibitor p27Pagano, MicheleTam, SWTheodoras, AMBeer-Romero, PDel Sal, GChau, VYew, PRDraetta, GFRolfe, MScience 269:682-5inferred from electronic annotationEVIDENCE CODEECO:0000203Reactome Database ID Release 7510488728Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10488728ReactomeR-GGA-25595861Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-GGA-2559586.1Reactive oxygen species (ROS), whose concentration increases in senescent cells due to oncogenic RAS-induced mitochondrial dysfunction (Moiseeva et al. 2009) or due to environmental stress, cause DNA damage in the form of double strand breaks (DSBs) (Yu and Anderson 1997). In addition, persistent cell division fueled by oncogenic signaling leads to replicative exhaustion, manifested in critically short telomeres (Harley et al. 1990, Hastie et al. 1990). Shortened telomeres are no longer able to bind the protective shelterin complex (Smogorzewska et al. 2000, de Lange 2005) and are recognized as damaged DNA. <p>The evolutionarily conserved MRN complex, consisting of MRE11A (MRE11), RAD50 and NBN (NBS1) subunits, binds DSBs (Lee and Paull 2005) and shortened telomeres that are no longer protected by shelterin (Wu et al. 2007). Once bound to the DNA, the MRN complex recruits and activates ATM kinase (Lee and Paull 2005, Wu et al. 2007), leading to phosphorylation of ATM targets, including TP53 (p53) (Banin et al. 1998, Canman et al. 1998, Khanna et al. 1998). TP53, phosphorylated on serine S15 by ATM, binds the CDKN1A (also known as p21, CIP1 or WAF1) promoter and induces CDKN1A transcription (El-Deiry et al. 1993, Karlseder et al. 1999). CDKN1A inhibits the activity of CDK2, leading to G1/S cell cycle arrest (Harper et al. 1993, El-Deiry et al. 1993).<p>SMURF2 is upregulated in response to telomere attrition in human fibroblasts and induces senecscent phenotype through RB1 and TP53, independently of its role in TGF-beta-1 signaling (Zhang and Cohen 2004). The exact mechanism of SMURF2 involvement is senescence has not been elucidated. 15790808Pubmed2005ATM activation by DNA double-strand breaks through the Mre11-Rad50-Nbs1 complexLee, JHPaull, TTScience 308:551-42342578Pubmed1990Telomeres shorten during ageing of human fibroblastsHarley, CBFutcher, ABGreider, CWNature 345:458-6010037601Pubmed1999p53- and ATM-dependent apoptosis induced by telomeres lacking TRF2Karlseder, JBroccoli, DDai, YHardy, Sde Lange, TScience 283:1321-59733514Pubmed1998Enhanced phosphorylation of p53 by ATM in response to DNA damage.Banin, SMoyal, LShieh, STaya, YAnderson, CWChessa, LSmorodinsky, NIPrives, CReiss, YShiloh, YZiv, YScience 281:1674-717694070Pubmed2007MRE11-RAD50-NBS1 and ATM function as co-mediators of TRF1 in telomere length controlWu, YiliXiao, ShujieZhu, Xu-DongNat. Struct. Mol. Biol. 14:832-408242752Pubmed1993WAF1, a potential mediator of p53 tumor suppression.el-Deiry, WSTokino, TVelculescu, VELevy, DBParsons, RTrent, JMLin, DMercer, WEKinzler, KWVogelstein, BCell 75:817-252392154Pubmed1990Telomere reduction in human colorectal carcinoma and with ageingHastie, N DDempster, MDunlop, M GThompson, A MGreen, D KAllshire, R CNature 346:866-816166375Pubmed2005Shelterin: the protein complex that shapes and safeguards human telomeresde Lange, TGenes Dev 19:2100-1010669743Pubmed2000Control of human telomere length by TRF1 and TRF2Smogorzewska, Avan Steensel, BBianchi, AOelmann, SSchaefer, M RSchnapp, Gde Lange, TMol. Cell. Biol. 20:1659-689733515Pubmed1998Activation of the ATM kinase by ionizing radiation and phosphorylation of p53.Canman, CELim, DSTaya, YTamai, KSakaguchi, KAppella, EKastan, MBSiliciano, JDScience 281:1677-99357549Pubmed1997Reactive oxygen species-induced DNA damage and its modification: a chemical investigationYu, T WAnderson, DMutat. Res. 379:201-1015574587Pubmed2004Smurf2 up-regulation activates telomere-dependent senescenceZhang, HCohen, Stanley NGenes Dev. 18:3028-409843217Pubmed1998ATM associates with and phosphorylates p53: mapping the region of interaction.Khanna, Kum KumKeating, KEKozlov, SScott, SGatei, MHobson, KTaya, YGabrielli, BChan, DLees-Miller, SPLavin, MFNat Genet 20:398-40019528227Pubmed2009Mitochondrial dysfunction contributes to oncogene-induced senescenceMoiseeva, OlgaBourdeau, VéroniqueRoux, AntoineDeschênes-Simard, XavierFerbeyre, GerardoMol. Cell. Biol. 29:4495-507