Senescence-Associated Secretory Phenotype (SASP) (Homo sapiens)

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4, 10, 19, 27, 37...12617, 27, 32, 46, 65...59, 95, 1026, 85, 105, 121, 12595504545049510250, 6217, 27, 32, 46, 50...5050, 937, 16, 45, 60, 69...76, 1027, 16, 45, 60, 69...50, 10827, 46, 65, 68, 76...27, 46, 50, 59, 65...cytosolnucleoplasmHIST1H2AC HIST1H2BB H2AFB1 H2AFX HIST1H2BK ANAPC10 HIST2H2AA3 HIST1H2BM H2BFS p-T160-CDK2 ANAPC15 HIST1H3A RPS6KA2 INK4UBC(457-532) Me2K-10-HIST2H3A HIST1H2AC UBE2C IL6 gene HIST1H2AJ ANAPC11 CCNA:p-T160-CDK2UBE2D1 HIST1H2BL ANAPC16 p-Y705-STAT3 dimerIGFBP7ANAPC11 CDC23 HIST1H2BO p-T185,Y187-MAPK1 HIST1H2BB HIST1H2BB EHMT1 EHMT2 H2AFV CDC16 UBC(609-684) H2AFB1 p-2S-cJUN:p-2S,2T-cFOSANAPC15 CDK4,CDK6UBC(77-152) H3F3A p-2S-JUN:p-2S,2T-FOS:IGFBP7 GeneCDC27 UBE2C UBC(457-532) H2BFS UBE2D1 p-T185,Y187-MAPK1 EHMT2 UBC(229-304) UBA52(1-76) HIST1H2AB RELA UBC(305-380) UBC(77-152) H2AFZ HIST2H2AC HIST1H2AD CDKN2BCDK4 CCNA1 UBB(77-152) HIST1H2BL ANAPC7 CDKN2B gene Me2K10-HIST1H3A HIST1H2BN Cdh1:phospho-APC/CcomplexANAPC4 HIST1H2BM ANAPC7 HIST1H2BM ATPANAPC5 p-T235-CEBPBADPIL8gene:Nucleosome-H3K9Me2HIST1H2BH Me2K-10-H3F3A IL6 geneCDKN2D HIST1H2AB H2AFB1 CDC27 UBE2E1 RPS27A(1-76) HIST2H3A CDC27 HIST1H2BH HIST1H2BN CDC23 AdoHcyHIST2H2AA3 UBB(153-228) p-2S-JUN:p-2S,2T-FOS:IL1A geneH2AFJ HIST2H2AC CDC23 ANAPC2 UbHIST1H2AB HIST1H2BN HIST1H4 p-S63,S73-JUN FZR1 p-T235, S321-CEBPBRPS6KA3 CCNA1 p-4S,T359,T573-RPS6KA1 CCNA2 H2AFB1 IL8 gene p-S63,S73-JUN CDKN2B geneUBE2C NFKB1(1-433) ATPHIST1H2BM HIST1H4 HIST1H2BK CDC16 H2AFZ p-T160-CDK2 HIST1H2AD p-Y705-STAT3 EHMT1 FZR1 IL8 gene H2BFS HIST1H2BK HIST3H2BB EHMT1:EHMT2HIST1H2AC ANAPC4 ANAPC4 ANAPC16 Oncogenic MAPKsignalingEHMT1:EHMT2:Cdh1:p-APC/CUBE2E1 HIST1H2AJ HIST2H2BE UBC(609-684) HIST1H2BD ANAPC2 H2AFX HIST1H2BO ANAPC10 HIST1H2BH HIST2H2BE ANAPC16 CDK4 ADPHIST1H2BD CDC26 IL1A gene p-T325,T331,S362,S374-FOS HIST1H2AC CDC26 CCNA2 HIST1H2BJ CDC16 IL6 gene p-4S,T356,T570-RPS6KA2 HIST1H2BD HIST1H3A CDC26 CDKN2B CyclinA:Cdk2:p21/p27complexp-T235,S321-CEBPB:NF-kB:IL6 geneUBA52(1-76) HIST3H2BB H2AFJ ANAPC2 p-T202,Y204-MAPK3 ANAPC16 p-T235, S321-CEBPB HIST2H2BE HIST1H2BA H2BFS HIST2H2AC p16-INK4a CyclinA:phospho-Cdk(Thr160):Cdh1:phosho-APC/C complexHIST1H2BC Phospho-Ribosomalprotein S6 kinaseHIST3H2BB AdoMetMe2K-10-H3F3A ANAPC1 HIST1H2BB ANAPC11 p-FZR1 CDK2 ANAPC5 UBC(153-228) p-T325,T331,S362,S374-FOS CCNA1 Me2K10-HIST1H3A UBE2E1 ANAPC15 UBB(1-76) HIST1H2BL ANAPC1 IL6ANAPC10 IL8ANAPC15 CDC27 H2AFV EHMT1 CDC16 Ribosomal protein S6kinaseANAPC1 CDC16 NFKB1(1-433) UBB(1-76) ATPMe2K-10-HIST2H3A IL6 gene EHMT2 ANAPC10 H3F3A HIST3H2BB p-T325,T331,S362,S374-FOS IL8 gene2xMyri-IL1AHIST1H2BJ ANAPC11 H2AFX ANAPC5 UBC(533-608) UBE2E1 p-S63,S73-JUN CDKN2C HIST1H2AD UBC(153-228) IGFBP7 gene HIST1H2AJ CDK6 ANAPC11 UBB(153-228) ANAPC7 ANAPC10 UBC(1-76) p-T235, S321-CEBPB UBC(533-608) HIST1H2BC UBE2C HIST2H2AA3 HIST1H2BC HIST1H4 HIST1H2BJ p-T235,S321-CEBPBhomodimerH2AFJ CEBPB geneANAPC4 UBE2C ANAPC5 H2AFJ UBC(229-304) CCNA2 IL1A geneUb-EHMT1:Ub-EHMT2:Cdh1:p-APC/CHIST1H2BH IL8 gene:NucleosomeNFKB1(1-433) HIST2H2BE CDC23 CDC26 CDKN2C p-T218,Y220-MAPK7 HIST1H2AJ UBC(381-456) UBE2D1 UBE2D1 HIST1H2AD DNA Damage/TelomereStress InducedSenescenceCyclinA:phospho-Cdk2(Thr160):phospho-Cdh1:phospho-APC/C complexInterleukin-6 familysignalingIGFBP7 geneADPANAPC5 H2AFX ANAPC1 p-T235, S321-CEBPB HIST1H2BD p-ERK1/2/5ANAPC1 HIST1H2BJ HIST1H2BL CDC26 HIST2H2AA3 RELA CDKN2D UBE2D1 UBE2E1 HIST1H2BO IL6 gene:NucleosomeHIST1H2BO UBC(1-76) CDK6 ANAPC16 H2AFZ HIST1H2BA FZR1 ANAPC15 IL8 gene CCNA1 p-T235, S321-CEBPB p-T,Y MAPK dimersH2AFZ Interleukin-1 familysignalingHIST1H4 p-T160-CDK2 ANAPC7 CDK4,CDK6:INK4CDKN2B p-T235,S321-CEBPB:NF-kB:IL8 GeneHIST1H2AB CDKN1A CDC27 UBC(305-380) ANAPC7 IL6gene:Nucleosome-H3K9Me2CDKN1B ANAPC4 RPS6KA1 ATPOncogene InducedSenescenceH2AFV CCNA2 HIST2H3A Oxidative StressInduced SenescenceCDC23 UBC(381-456) p-4S,T231,T365-RPS6KA3 RPS27A(1-76) ANAPC2 HIST1H2BC FZR1 CEBPBNF-kB complexHIST1H2BN H2AFV p-T202,Y204-MAPK3 RELA ADPANAPC2 HIST1H2BK p16-INK4a HIST1H2BA HIST1H2BA HIST2H2AC p-T235,S321-CEBPB:CDKN2B GeneUBB(77-152) 9571, 1132, 21, 23, 41, 103...12, 13, 22, 24, 28...18, 25, 35, 40, 49...3, 5, 8, 9, 11...501, 20, 44, 52, 53, 67...93495509676, 102IGFBP6IGFBP3IGFBP5IGFBP1CTGF127IGFBP7IGFBP4IGFBP2


Description

The culture medium of senescent cells in enriched in secreted proteins when compared with the culture medium of quiescent i.e. presenescent cells and these secreted proteins constitute the so-called senescence-associated secretory phenotype (SASP), also known as the senescence messaging secretome (SMS). SASP components include inflammatory and immune-modulatory cytokines (e.g. IL6 and IL8), growth factors (e.g. IGFBPs), shed cell surface molecules (e.g. TNF receptors) and survival factors. While the SASP exhibits a wide ranging profile, it is not significantly affected by the type of senescence trigger (oncogenic signalling, oxidative stress or DNA damage) or the cell type (epithelial vs. mesenchymal) (Coppe et al. 2008). However, as both oxidative stress and oncogenic signaling induce DNA damage, the persistent DNA damage may be a deciding SASP initiator (Rodier et al. 2009). SASP components function in an autocrine manner, reinforcing the senescent phenotype (Kuilman et al. 2008, Acosta et al. 2008), and in the paracrine manner, where they may promote epithelial-to-mesenchymal transition (EMT) and malignancy in the nearby premalignant or malignant cells (Coppe et al. 2008). Interleukin-1-alpha (IL1A), a minor SASP component whose transcription is stimulated by the AP-1 (FOS:JUN) complex (Bailly et al. 1996), can cause paracrine senescence through IL1 and inflammasome signaling (Acosta et al. 2013).

Here, transcriptional regulatory processes that mediate the SASP are annotated. DNA damage triggers ATM-mediated activation of TP53, resulting in the increased level of CDKN1A (p21). CDKN1A-mediated inhibition of CDK2 prevents phosphorylation and inactivation of the Cdh1:APC/C complex, allowing it to ubiquitinate and target for degradation EHMT1 and EHMT2 histone methyltransferases. As EHMT1 and EHMT2 methylate and silence the promoters of IL6 and IL8 genes, degradation of these methyltransferases relieves the inhibition of IL6 and IL8 transcription (Takahashi et al. 2012). In addition, oncogenic RAS signaling activates the CEBPB (C/EBP-beta) transcription factor (Nakajima et al. 1993, Lee et al. 2010), which binds promoters of IL6 and IL8 genes and stimulates their transcription (Kuilman et al. 2008, Lee et al. 2010). CEBPB also stimulates the transcription of CDKN2B (p15-INK4B), reinforcing the cell cycle arrest (Kuilman et al. 2008). CEBPB transcription factor has three isoforms, due to three alternative translation start sites. The CEBPB-1 isoform (C/EBP-beta-1) seems to be exclusively involved in growth arrest and senescence, while the CEBPB-2 (C/EBP-beta-2) isoform may promote cellular proliferation (Atwood and Sealy 2010 and 2011). IL6 signaling stimulates the transcription of CEBPB (Niehof et al. 2001), creating a positive feedback loop (Kuilman et al. 2009, Lee et al. 2010). NF-kappa-B transcription factor is also activated in senescence (Chien et al. 2011) through IL1 signaling (Jimi et al. 1996, Hartupee et al. 2008, Orjalo et al. 2009). NF-kappa-B binds IL6 and IL8 promoters and cooperates with CEBPB transcription factor in the induction of IL6 and IL8 transcription (Matsusaka et al. 1993, Acosta et al. 2008). Besides IL6 and IL8, their receptors are also upregulated in senescence (Kuilman et al. 2008, Acosta et al. 2008) and IL6 and IL8 may be master regulators of the SASP.<p>IGFBP7 is also an SASP component that is upregulated in response to oncogenic RAS-RAF-MAPK signaling and oxidative stress, as its transcription is directly stimulated by the AP-1 (JUN:FOS) transcription factor. IGFBP7 negatively regulates RAS-RAF (BRAF)-MAPK signaling and is important for the establishment of senescence in melanocytes (Wajapeyee et al. 2008).<p>Please refer to Young and Narita 2009 for a recent review. View original pathway at:Reactome.</div>

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Reactome-Converter 
Pathway is converted from Reactome ID: 2559582
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Reactome version: 61
Reactome Author 
Reactome Author: Orlic-Milacic, Marija

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  91. Deacon K, Blank JL.; ''Characterization of the mitogen-activated protein kinase kinase 4 (MKK4)/c-Jun NH2-terminal kinase 1 and MKK3/p38 pathways regulated by MEK kinases 2 and 3. MEK kinase 3 activates MKK3 but does not cause activation of p38 kinase in vivo.''; PubMed Europe PMC
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  93. Karlseder J, Broccoli D, Dai Y, Hardy S, de Lange T.; ''p53- and ATM-dependent apoptosis induced by telomeres lacking TRF2.''; PubMed Europe PMC
  94. Lee JH, Paull TT.; ''ATM activation by DNA double-strand breaks through the Mre11-Rad50-Nbs1 complex.''; PubMed Europe PMC
  95. Bailly S, Fay M, Israël N, Gougerot-Pocidalo MA.; ''The transcription factor AP-1 binds to the human interleukin 1 alpha promoter.''; PubMed Europe PMC
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  97. Lee S, Shuman JD, Guszczynski T, Sakchaisri K, Sebastian T, Copeland TD, Miller M, Cohen MS, Taunton J, Smart RC, Xiao Z, Yu LR, Veenstra TD, Johnson PF.; ''RSK-mediated phosphorylation in the C/EBP{beta} leucine zipper regulates DNA binding, dimerization, and growth arrest activity.''; PubMed Europe PMC
  98. Parisi T, Pollice A, Di Cristofano A, Calabrò V, La Mantia G.; ''Transcriptional regulation of the human tumor suppressor p14(ARF) by E2F1, E2F2, E2F3, and Sp1-like factors.''; PubMed Europe PMC
  99. Ichijo H, Nishida E, Irie K, ten Dijke P, Saitoh M, Moriguchi T, Takagi M, Matsumoto K, Miyazono K, Gotoh Y.; ''Induction of apoptosis by ASK1, a mammalian MAPKKK that activates SAPK/JNK and p38 signaling pathways.''; PubMed Europe PMC
  100. Lal A, Kim HH, Abdelmohsen K, Kuwano Y, Pullmann R, Srikantan S, Subrahmanyam R, Martindale JL, Yang X, Ahmed F, Navarro F, Dykxhoorn D, Lieberman J, Gorospe M.; ''p16(INK4a) translation suppressed by miR-24.''; PubMed Europe PMC
  101. Kuilman T, Michaloglou C, Vredeveld LC, Douma S, van Doorn R, Desmet CJ, Aarden LA, Mooi WJ, Peeper DS.; ''Oncogene-induced senescence relayed by an interleukin-dependent inflammatory network.''; PubMed Europe PMC
  102. Hartupee J, Li X, Hamilton T.; ''Interleukin 1alpha-induced NFkappaB activation and chemokine mRNA stabilization diverge at IRAK1.''; PubMed Europe PMC
  103. Kishimoto T.; ''IL-6: from its discovery to clinical applications.''; PubMed Europe PMC
  104. Parry D, Bates S, Mann DJ, Peters G.; ''Lack of cyclin D-Cdk complexes in Rb-negative cells correlates with high levels of p16INK4/MTS1 tumour suppressor gene product.''; PubMed Europe PMC
  105. Yang BS, Hauser CA, Henkel G, Colman MS, Van Beveren C, Stacey KJ, Hume DA, Maki RA, Ostrowski MC.; ''Ras-mediated phosphorylation of a conserved threonine residue enhances the transactivation activities of c-Ets1 and c-Ets2.''; PubMed Europe PMC
  106. Guan KL, Jenkins CW, Li Y, O'Keefe CL, Noh S, Wu X, Zariwala M, Matera AG, Xiong Y.; ''Isolation and characterization of p19INK4d, a p16-related inhibitor specific to CDK6 and CDK4.''; PubMed Europe PMC
  107. Agherbi H, Gaussmann-Wenger A, Verthuy C, Chasson L, Serrano M, Djabali M.; ''Polycomb mediated epigenetic silencing and replication timing at the INK4a/ARF locus during senescence.''; PubMed Europe PMC
  108. Bracken AP, Pasini D, Capra M, Prosperini E, Colli E, Helin K.; ''EZH2 is downstream of the pRB-E2F pathway, essential for proliferation and amplified in cancer.''; PubMed Europe PMC
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  110. Moiseeva O, Mallette FA, Mukhopadhyay UK, Moores A, Ferbeyre G.; ''DNA damage signaling and p53-dependent senescence after prolonged beta-interferon stimulation.''; PubMed Europe PMC
  111. Moiseeva O, Bourdeau V, Roux A, Deschênes-Simard X, Ferbeyre G.; ''Mitochondrial dysfunction contributes to oncogene-induced senescence.''; PubMed Europe PMC
  112. Kunsch C, Rosen CA.; ''NF-kappa B subunit-specific regulation of the interleukin-8 promoter.''; PubMed Europe PMC
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  118. Dietrich N, Bracken AP, Trinh E, Schjerling CK, Koseki H, Rappsilber J, Helin K, Hansen KH.; ''Bypass of senescence by the polycomb group protein CBX8 through direct binding to the INK4A-ARF locus.''; PubMed Europe PMC
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  121. Zhang Y, Xiong Y, Yarbrough WG.; ''ARF promotes MDM2 degradation and stabilizes p53: ARF-INK4a locus deletion impairs both the Rb and p53 tumor suppression pathways.''; PubMed Europe PMC
  122. Hannon GJ, Beach D.; ''p15INK4B is a potential effector of TGF-beta-induced cell cycle arrest.''; PubMed Europe PMC
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History

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CompareRevisionActionTimeUserComment
101427view11:30, 1 November 2018ReactomeTeamreactome version 66
100965view21:07, 31 October 2018ReactomeTeamreactome version 65
100502view19:42, 31 October 2018ReactomeTeamreactome version 64
100048view16:25, 31 October 2018ReactomeTeamreactome version 63
99600view14:59, 31 October 2018ReactomeTeamreactome version 62 (2nd attempt)
99216view12:44, 31 October 2018ReactomeTeamreactome version 62
96095view21:17, 15 February 2018VjlynchAdded IGFBP genes
93504view11:25, 9 August 2017ReactomeTeamreactome version 61
86599view09:21, 11 July 2016ReactomeTeamreactome version 56
83199view10:21, 18 November 2015ReactomeTeamVersion54
81577view13:07, 21 August 2015ReactomeTeamNew pathway

External references

DataNodes

View all...
NameTypeDatabase referenceComment
2xMyri-IL1AProteinP01583 (Uniprot-TrEMBL)
ADPMetaboliteCHEBI:16761 (ChEBI)
ANAPC1 ProteinQ9H1A4 (Uniprot-TrEMBL)
ANAPC10 ProteinQ9UM13 (Uniprot-TrEMBL)
ANAPC11 ProteinQ9NYG5 (Uniprot-TrEMBL)
ANAPC15 ProteinP60006 (Uniprot-TrEMBL)
ANAPC16 ProteinQ96DE5 (Uniprot-TrEMBL)
ANAPC2 ProteinQ9UJX6 (Uniprot-TrEMBL)
ANAPC4 ProteinQ9UJX5 (Uniprot-TrEMBL)
ANAPC5 ProteinQ9UJX4 (Uniprot-TrEMBL)
ANAPC7 ProteinQ9UJX3 (Uniprot-TrEMBL)
ATPMetaboliteCHEBI:15422 (ChEBI)
AdoHcyMetaboliteCHEBI:16680 (ChEBI)
AdoMetMetaboliteCHEBI:15414 (ChEBI)
CCNA1 ProteinP78396 (Uniprot-TrEMBL)
CCNA2 ProteinP20248 (Uniprot-TrEMBL)
CCNA:p-T160-CDK2ComplexR-HSA-187952 (Reactome)
CDC16 ProteinQ13042 (Uniprot-TrEMBL)
CDC23 ProteinQ9UJX2 (Uniprot-TrEMBL)
CDC26 ProteinQ8NHZ8 (Uniprot-TrEMBL)
CDC27 ProteinP30260 (Uniprot-TrEMBL)
CDK2 ProteinP24941 (Uniprot-TrEMBL)
CDK4 ProteinP11802 (Uniprot-TrEMBL)
CDK4,CDK6:INK4ComplexR-HSA-182579 (Reactome)
CDK4,CDK6ComplexR-HSA-69209 (Reactome)
CDK6 ProteinQ00534 (Uniprot-TrEMBL)
CDKN1A ProteinP38936 (Uniprot-TrEMBL)
CDKN1B ProteinP46527 (Uniprot-TrEMBL)
CDKN2B ProteinP42772 (Uniprot-TrEMBL)
CDKN2B gene ProteinENSG00000147883 (Ensembl)
CDKN2B geneGeneProductENSG00000147883 (Ensembl)
CDKN2BProteinP42772 (Uniprot-TrEMBL)
CDKN2C ProteinP42773 (Uniprot-TrEMBL)
CDKN2D ProteinP55273 (Uniprot-TrEMBL)
CEBPB geneGeneProductENSG00000172216 (Ensembl)
CEBPBProteinP17676 (Uniprot-TrEMBL)
CTGFGeneProduct1490 (Entrez Gene)
Cdh1:phospho-APC/C complexComplexR-HSA-174250 (Reactome)
Cyclin

A:Cdk2:p21/p27

complex
ComplexR-HSA-187926 (Reactome)
Cyclin

A:phospho-Cdk(Thr

160):Cdh1:phosho-APC/C complex
ComplexR-HSA-188374 (Reactome)
Cyclin

A:phospho-Cdk2(Thr

160):phospho-Cdh1:phospho-APC/C complex
ComplexR-HSA-188387 (Reactome)
DNA Damage/Telomere

Stress Induced

Senescence
PathwayR-HSA-2559586 (Reactome) Reactive 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.

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).

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.

EHMT1 ProteinQ9H9B1 (Uniprot-TrEMBL)
EHMT1:EHMT2:Cdh1:p-APC/CComplexR-HSA-3788733 (Reactome)
EHMT1:EHMT2ComplexR-HSA-3788728 (Reactome)
EHMT2 ProteinQ96KQ7 (Uniprot-TrEMBL)
FZR1 ProteinQ9UM11 (Uniprot-TrEMBL)
H2AFB1 ProteinP0C5Y9 (Uniprot-TrEMBL)
H2AFJ ProteinQ9BTM1 (Uniprot-TrEMBL)
H2AFV ProteinQ71UI9 (Uniprot-TrEMBL)
H2AFX ProteinP16104 (Uniprot-TrEMBL)
H2AFZ ProteinP0C0S5 (Uniprot-TrEMBL)
H2BFS ProteinP57053 (Uniprot-TrEMBL)
H3F3A ProteinP84243 (Uniprot-TrEMBL)
HIST1H2AB ProteinP04908 (Uniprot-TrEMBL)
HIST1H2AC ProteinQ93077 (Uniprot-TrEMBL)
HIST1H2AD ProteinP20671 (Uniprot-TrEMBL)
HIST1H2AJ ProteinQ99878 (Uniprot-TrEMBL)
HIST1H2BA ProteinQ96A08 (Uniprot-TrEMBL)
HIST1H2BB ProteinP33778 (Uniprot-TrEMBL)
HIST1H2BC ProteinP62807 (Uniprot-TrEMBL)
HIST1H2BD ProteinP58876 (Uniprot-TrEMBL)
HIST1H2BH ProteinQ93079 (Uniprot-TrEMBL)
HIST1H2BJ ProteinP06899 (Uniprot-TrEMBL)
HIST1H2BK ProteinO60814 (Uniprot-TrEMBL)
HIST1H2BL ProteinQ99880 (Uniprot-TrEMBL)
HIST1H2BM ProteinQ99879 (Uniprot-TrEMBL)
HIST1H2BN ProteinQ99877 (Uniprot-TrEMBL)
HIST1H2BO ProteinP23527 (Uniprot-TrEMBL)
HIST1H3A ProteinP68431 (Uniprot-TrEMBL)
HIST1H4 ProteinP62805 (Uniprot-TrEMBL)
HIST2H2AA3 ProteinQ6FI13 (Uniprot-TrEMBL)
HIST2H2AC ProteinQ16777 (Uniprot-TrEMBL)
HIST2H2BE ProteinQ16778 (Uniprot-TrEMBL)
HIST2H3A ProteinQ71DI3 (Uniprot-TrEMBL)
HIST3H2BB ProteinQ8N257 (Uniprot-TrEMBL)
IGFBP1GeneProduct3484 (Entrez Gene)
IGFBP2GeneProductIGFBP2 (HGNC)
IGFBP3GeneProductIGFBP3 (HGNC)
IGFBP4GeneProductIGFBP4 (HGNC)
IGFBP5GeneProductIGFBP5 (HGNC)
IGFBP6GeneProductIGFBP6 (HGNC)
IGFBP7 gene ProteinENSG00000163453 (Ensembl)
IGFBP7 geneGeneProductENSG00000163453 (Ensembl)
IGFBP7GeneProduct3490 (Entrez Gene)
IGFBP7ProteinQ16270 (Uniprot-TrEMBL)
IL1A gene ProteinENSG00000115008 (Ensembl)
IL1A geneGeneProductENSG00000115008 (Ensembl)
IL6 gene:Nucleosome-H3K9Me2ComplexR-HSA-3788744 (Reactome)
IL6 gene ProteinENSG00000136244 (Ensembl)
IL6 gene:NucleosomeComplexR-HSA-3788741 (Reactome)
IL6 geneGeneProductENSG00000136244 (Ensembl)
IL6ProteinP05231 (Uniprot-TrEMBL)
IL8 gene:Nucleosome-H3K9Me2ComplexR-HSA-3788746 (Reactome)
IL8 gene ProteinENSG00000169429 (Ensembl)
IL8 gene:NucleosomeComplexR-HSA-3788743 (Reactome)
IL8 geneGeneProductENSG00000169429 (Ensembl)
IL8ProteinP10145 (Uniprot-TrEMBL)
INK4ComplexR-HSA-182588 (Reactome)
Interleukin-1 family signalingPathwayR-HSA-446652 (Reactome) Interleukin 1 (IL1) signals via Interleukin 1 receptor 1 (IL1R1), the only signaling-capable IL1 receptor. This is a single chain type 1 transmembrane protein comprising an extracellular ligand binding domain and an intracellular region called the Toll/Interleukin-1 receptor (TIR) domain that is structurally conserved and shared by other members of the two families of receptors (Xu et al. 2000). This domain is also shared by the downstream adapter molecule MyD88. IL1 binding to IL1R1 leads to the recruitment of a second receptor chain termed the IL1 receptor accessory protein (IL1RAP or IL1RAcP) enabling the formation of a high-affinity ligand-receptor complex that is capable of signal transduction. Intracellular signaling is initiated by the recruitment of MyD88 to the IL-1R1/IL1RAP complex. IL1RAP is only recruited to IL1R1 when IL1 is present; it is believed that a TIR domain signaling complex is formed between the receptor and the adapter TIR domains. The recruitment of MyD88 leads to the recruitment of Interleukin-1 receptor-associated kinase (IRAK)-1 and -4, probably via their death domains. IRAK4 then activates IRAK1, allowing IRAK1 to autophosphorylate. Both IRAK1 and IRAK4 then dissociate from MyD88 (Brikos et al. 2007) which remains stably complexed with IL-1R1 and IL1RAP. They in turn interact with Tumor Necrosis Factor Receptor (TNFR)-Associated Factor 6 (TRAF6), which is an E3 ubiquitin ligase (Deng et al. 2000). TRAF6 is then thought to auto-ubiquinate, attaching K63-polyubiquitin to itself with the assistance of the E2 conjugating complex Ubc13/Uev1a. K63-pUb-TRAF6 recruits Transforming Growth Factor (TGF) beta-activated protein kinase 1 (TAK1) in a complex with TAK1-binding protein 2 (TAB2) and TAB3, which both contain nuclear zinc finger motifs that interact with K63-polyubiquitin chains (Ninomiya-Tsuji et al. 1999). This activates TAK1, which then activates inhibitor of NF-kappaB (IkappaB) kinase 2 (IKK2 or IKKB) within the IKK complex, the kinase responsible for phosphorylation of IkappaB. The IKK complex also contains the scaffold protein NF-kappa B essential modulator (NEMO). TAK1 also couples to the upstream kinases for p38 and c-jun N-terminal kinase (JNK). IRAK1 undergoes K63-linked polyubiquination; Pellino E3 ligases are important in this process. (Butler et al. 2007; Ordureau et al. 2008). The activity of these proteins is greatly enhanced by IRAK phosphorylation (Schauvliege et al. 2006), leading to K63-linked polyubiquitination of IRAK1. This recruits NEMO to IRAK1, with NEMO binding to polyubiquitin (Conze et al. 2008).

TAK1 activates IKKB (and IKK), resulting in phosphorylation of the inhibitory IkB proteins and enabling translocation of NFkB to the nucleus; IKKB also phosphorylates NFkB p105, leading to its degradation and the subsequent release of active TPL2 that triggers the extracellular-signal regulated kinase (ERK)1/2 MAPK cascade. TAK1 can also trigger the p38 and JNK MAPK pathways via activating the upstream MKKs3, 4 and 6. The MAPK pathways activate a number of downstream kinases and transcription factors that co-operate with NFkB to induce the expression of a range of TLR/IL-1R-responsive genes. There are reports suggesting that IL1 stimulation increases nuclear localization of IRAK1 (Bol et al. 2000) and that nuclear IRAK1 binds to the promoter of NFkB-regulated gene and IkBa, enhancing binding of the NFkB p65 subunit to NFkB responsive elements within the IkBa promoter. IRAK1 is required for IL1-induced Ser-10 phosphorylation of histone H3 in vivo (Liu et al. 2008). However, details of this aspect of IRAK1 signaling mechanisms remain unclear.
Interleukin-6 family signalingPathwayR-HSA-6783589 (Reactome) The interleukin-6 (IL6) family of cytokines includes IL6, IL11, IL27, leukemia inhibitory factor (LIF), oncostatin M (OSM), ciliary neurotrophic factor (CNTF), cardiotrophin 1 and 2 (CT-1) and cardiotrophin-like cytokine (CLC) (Heinrich et al. 2003, Pflanz et al. 2002). The latest addition to this family is IL31, discovered in 2004 (Dillon et al. 2004). The family is defined largely by the shared use of the common signal transducing receptor Interleukin-6 receptor subunit beta (IL6ST, gp130). The IL31 receptor uniquely does not include this subunit, instead it uses the related IL31RA. The members of the IL6 family share very low sequence homology but are structurally highly related, forming anti-parallel four-helix bundles with a characteristic “up-up-down-down� topology (Rozwarski et al. 1994, Cornelissen et al. 2012).

Although each member of the IL6 family signals through a distinct receptor complex, their underlying signaling mechanisms are similar. Assembly of the receptor complex is followed by activation of receptor-associated Janus kinases (JAKs), believed to be constitutively associated with the receptor subunits.Activation of JAKs initiates downstream cytoplasmic signaling cascades that involve recruitment and phosphorylation of transcription factors of the Signal transducer and activator of transcription (STAT) family, which dimerize and translocate to the nucleus where they bind enhancer elements of target genes leading to transcriptional activation (Nakashima & Taga 1998).

Negative regulators of IL-6 signaling include Suppressor of cytokine signals (SOCS) family members and PTPN11 (SHP-2).

IL6 is a pleiotropic cytokine with roles in processes including immune regulation, hematopoiesis, inflammation, oncogenesis, metabolic control and sleep.

IL6 and IL11 bind their corresponding specific receptors IL6R and IL11R respectively, resulting in dimeric complexes that associate with IL6ST, leading to IL6ST homodimer formation and signal initiation. IL6R alpha exists in transmembrane and soluble forms. The transmembrane form is mainly expressed by hepatocytes, neutrophils, monocytes/macrophages, and some lymphocytes. Soluble forms of IL6R (sIL6R) are also expressed by these cells. Two major mechanisms for the production of sIL6R have been proposed. Alternative splicing generates a transcript lacking the transmembrane domain by using splicing donor and acceptor sites that flank the transmembrane domain coding region. This also introduces a frameshift leading to the incorporation of 10 additional amino acids at the C terminus of sIL6R.A second mechanism for the generation of sIL6R is the proteolytic cleavage or 'shedding' of membrane-bound IL-6R. Two proteases ADAM10 and ADAM17 are thought to contribute to this (Briso et al. 2008). sIL6R can bind IL6 and stimulate cells that express gp130 but not IL6R alpha, a process that is termed trans-signaling. This explains why many cells, including hematopoietic progenitor cells, neuronal cells, endothelial cells, smooth muscle cells, and embryonic stem cells, do not respond to IL6 alone, but show a remarkable response to IL6/sIL6R. It is clear that the trans-signaling pathway is responsible for the pro-inflammatory activities of IL6 whereas the membrane bound receptor governs regenerative and anti-inflammatory IL6 activities

LIF, CNTF, OSM, CTF1, CRLF1 and CLCF1 signal via IL6ST:LIFR heterodimeric receptor complexes (Taga & Kishimoto 1997, Mousa & Bakhiet 2013). OSM signals via a receptor complex consisting of IL6ST and OSMR. These cytokines play important roles in the regulation of complex cellular processes such as gene activation, proliferation and differentiation (Heinrich et al. 1998).

Antibodies have been developed to inhibit IL6 activity for the treatment of inflammatory diseases (Kopf et al. 2010).
Me2K-10-H3F3A ProteinP84243 (Uniprot-TrEMBL)
Me2K-10-HIST2H3A ProteinQ71DI3 (Uniprot-TrEMBL)
Me2K10-HIST1H3A ProteinP68431 (Uniprot-TrEMBL)
NF-kB complexComplexR-HSA-194047 (Reactome)
NFKB1(1-433) ProteinP19838 (Uniprot-TrEMBL)
Oncogene Induced SenescencePathwayR-HSA-2559585 (Reactome) Oncogene-induced senescence is triggered by high level of RAS/RAF/MAPK signaling that can be caused, for example, by oncogenic mutations in RAS or RAF proteins, or by oncogenic mutations in growth factor receptors, such as EGFR, that act upstream of RAS/RAF/MAPK cascade. Oncogene-induced senescence can also be triggered by high transcriptional activity of E2F1, E2F2 or E2F3 which can be caused, for example, by the loss-of-function of RB1 tumor suppressor.

Oncogenic signals trigger transcription of CDKN2A locus tumor suppressor genes: p16-INK4A and p14-ARF. p16-INK4A and p14-ARF share exons 2 and 3, but are expressed from different promoters and use different reading frames (Quelle et al. 1995). Therefore, while their mRNAs are homologous and are both translationally inhibited by miR-24 microRNA (Lal et al. 2008, To et al. 2012), they share no similarity at the amino acid sequence level and perform distinct functions in the cell. p16-INK4A acts as the inhibitor of cyclin-dependent kinases CDK4 and CDK6 which phosphorylate and inhibit RB1 protein thereby promoting G1 to S transition and cell cycle progression (Serrano et al. 1993). Increased p16-INK4A level leads to hypophosphorylation of RB1, allowing RB1 to inhibit transcription of E2F1, E2F2 and E2F3-target genes that are needed for cell cycle progression, which results in cell cycle arrest in G1 phase. p14-ARF binds and destabilizes MDM2 ubiquitin ligase (Zhang et al. 1998), responsible for ubiquitination and degradation of TP53 (p53) tumor suppressor protein (Wu et al. 1993, Fuchs et al. 1998, Fang et al. 2000). Therefore, increased p14-ARF level leads to increased level of TP53 and increased expression of TP53 target genes, such as p21, which triggers p53-mediated cell cycle arrest and, depending on other factors, may also lead to p53-mediated apoptosis. CDKN2B locus, which encodes an inhibitor of CDK4 and CDK6, p15-INK4B, is located in the vicinity of CDKN2A locus, at the chromosome band 9p21. p15-INK4B, together with p16-INK4A, contributes to senescence of human T-lymphocytes (Erickson et al. 1998) and mouse fibroblasts (Malumbres et al. 2000). SMAD3, activated by TGF-beta-1 signaling, controls senescence in the mouse multistage carcinogenesis model through regulation of MYC and p15-INK4B gene expression (Vijayachandra et al. 2003). TGF-beta-induced p15-INK4B expression is also important for the senescence of hepatocellular carcinoma cell lines (Senturk et al. 2010).

MAP kinases MAPK1 (ERK2) and MAPK3 (ERK1), which are activated by RAS signaling, phosphorylate ETS1 and ETS2 transcription factors in the nucleus (Yang et al. 1996, Seidel et al. 2002, Foulds et al. 2004, Nelson et al. 2010). Phosphorylated ETS1 and ETS2 are able to bind RAS response elements (RREs) in the CDKN2A locus and stimulate p16-INK4A transcription (Ohtani et al. 2004). At the same time, activated ERKs (MAPK1 i.e. ERK2 and MAPK3 i.e. ERK1) phosphorylate ERF, the repressor of ETS2 transcription, which leads to translocation of ERF to the cytosol and increased transcription of ETS2 (Sgouras et al. 1995, Le Gallic et al. 2004). ETS2 can be sequestered and inhibited by binding to ID1, resulting in inhibition of p16-INK4A transcription (Ohtani et al. 2004).

Transcription of p14-ARF is stimulated by binding of E2F transcription factors (E2F1, E2F2 or E2F3) in complex with SP1 to p14-ARF promoter (Parisi et al. 2002).

Oncogenic RAS signaling affects mitochondrial metabolism through an unknown mechanism, leading to increased generation of reactive oxygen species (ROS), which triggers oxidative stress induced senescence pathway. In addition, increased rate of cell division that is one of the consequences of oncogenic signaling, leads to telomere shortening which acts as another senescence trigger.

Oncogenic MAPK signalingPathwayR-HSA-6802957 (Reactome) The importance of the RAS/RAF/MAPK cascade in regulating cellular proliferation, differentiation and survival is highlighted by the fact that components of the pathway are mutated with high frequency in a large number of human cancers. Activating mutations in RAS are found in approximately one third of human cancers, while ~8% of tumors express an activated form of BRAF. RAS pathway activation is also achieved in a smaller subset of cancers by loss-of-function mutations in negative regulators of RAS signaling, such as the RAS GAP NF1(reviewed in Prior et al, 2012; Pylayeva-Gupta et al, 2011; Stephen et al, 2014; Lavoie and Therrien, 2015; Lito et al, 2013; Samatar and Poulikakos, 2014; Maertens and Cichowski, 2014).
Oxidative Stress Induced SenescencePathwayR-HSA-2559580 (Reactome) Oxidative stress, caused by increased concentration of reactive oxygen species (ROS) in the cell, can happen as a consequence of mitochondrial dysfunction induced by the oncogenic RAS (Moiseeva et al. 2009) or independent of oncogenic signaling. Prolonged exposure to interferon-beta (IFNB, IFN-beta) also results in ROS increase (Moiseeva et al. 2006). ROS oxidize thioredoxin (TXN), which causes TXN to dissociate from the N-terminus of MAP3K5 (ASK1), enabling MAP3K5 to become catalytically active (Saitoh et al. 1998). ROS also stimulate expression of Ste20 family kinases MINK1 (MINK) and TNIK through an unknown mechanism, and MINK1 and TNIK positively regulate MAP3K5 activation (Nicke et al. 2005).


MAP3K5 phosphorylates and activates MAP2K3 (MKK3) and MAP2K6 (MKK6) (Ichijo et al. 1997, Takekawa et al. 2005), which act as p38 MAPK kinases, as well as MAP2K4 (SEK1) (Ichijo et al. 1997, Matsuura et al. 2002), which, together with MAP2K7 (MKK7), acts as a JNK kinase.


MKK3 and MKK6 phosphorylate and activate p38 MAPK alpha (MAPK14) and beta (MAPK11) (Raingeaud et al. 1996), enabling p38 MAPKs to phosphorylate and activate MAPKAPK2 (MK2) and MAPKAPK3 (MK3) (Ben-Levy et al. 1995, Clifton et al. 1996, McLaughlin et al. 1996, Sithanandam et al. 1996, Meng et al. 2002, Lukas et al. 2004, White et al. 2007), as well as MAPKAPK5 (PRAK) (New et al. 1998 and 2003, Sun et al. 2007).


Phosphorylation of JNKs (MAPK8, MAPK9 and MAPK10) by MAP3K5-activated MAP2K4 (Deacon and Blank 1997, Fleming et al. 2000) allows JNKs to migrate to the nucleus (Mizukami et al. 1997) where they phosphorylate JUN. Phosphorylated JUN binds FOS phosphorylated by ERK1 or ERK2, downstream of activated RAS (Okazaki and Sagata 1995, Murphy et al. 2002), forming the activated protein 1 (AP-1) complex (FOS:JUN heterodimer) (Glover and Harrison 1995, Ainbinder et al. 1997).


Activation of p38 MAPKs and JNKs downstream of MAP3K5 (ASK1) ultimately converges on transcriptional regulation of CDKN2A locus. In dividing cells, nucleosomes bound to the CDKN2A locus are trimethylated on lysine residue 28 of histone H3 (HIST1H3A) by the Polycomb repressor complex 2 (PRC2), creating the H3K27Me3 (Me3K-28-HIST1H3A) mark (Bracken et al. 2007, Kotake et al. 2007). The expression of Polycomb constituents of PRC2 (Kuzmichev et al. 2002) - EZH2, EED and SUZ12 - and thereby formation of the PRC2, is positively regulated in growing cells by E2F1, E2F2 and E2F3 (Weinmann et al. 2001, Bracken et al. 2003). H3K27Me3 mark serves as a docking site for the Polycomb repressor complex 1 (PRC1) that contains BMI1 (PCGF4) and is therefore named PRC1.4, leading to the repression of transcription of p16-INK4A and p14-ARF from the CDKN2A locus, where PCR1.4 mediated repression of p14-ARF transcription in humans may be context dependent (Voncken et al. 2005, Dietrich et al. 2007, Agherbi et al. 2009, Gao et al. 2012). MAPKAPK2 and MAPKAPK3, activated downstream of the MAP3K5-p38 MAPK cascade, phosphorylate BMI1 of the PRC1.4 complex, leading to dissociation of PRC1.4 complex from the CDKN2A locus and upregulation of p14-ARF transcription (Voncken et al. 2005). AP-1 transcription factor, formed as a result of MAP3K5-JNK signaling, as well as RAS signaling, binds the promoter of KDM6B (JMJD3) gene and stimulates KDM6B expression. KDM6B is a histone demethylase that removes H3K27Me3 mark i.e. demethylates lysine K28 of HIST1H3A, thereby preventing PRC1.4 binding to the CDKN2A locus and allowing transcription of p16-INK4A (Agger et al. 2009, Barradas et al. 2009, Lin et al. 2012).


p16-INK4A inhibits phosphorylation-mediated inactivation of RB family members by CDK4 and CDK6, leading to cell cycle arrest (Serrano et al. 1993). p14-ARF inhibits MDM2-mediated degradation of TP53 (p53) (Zhang et al. 1998), which also contributes to cell cycle arrest in cells undergoing oxidative stress. In addition, phosphorylation of TP53 by MAPKAPK5 (PRAK) activated downstream of MAP3K5-p38 MAPK signaling, activates TP53 and contributes to cellular senescence (Sun et al. 2007).

Phospho-Ribosomal protein S6 kinaseComplexR-HSA-199849 (Reactome)
RELA ProteinQ04206 (Uniprot-TrEMBL)
RPS27A(1-76) ProteinP62979 (Uniprot-TrEMBL)
RPS6KA1 ProteinQ15418 (Uniprot-TrEMBL)
RPS6KA2 ProteinQ15349 (Uniprot-TrEMBL)
RPS6KA3 ProteinP51812 (Uniprot-TrEMBL)
Ribosomal protein S6 kinaseComplexR-HSA-199858 (Reactome)
UBA52(1-76) ProteinP62987 (Uniprot-TrEMBL)
UBB(1-76) ProteinP0CG47 (Uniprot-TrEMBL)
UBB(153-228) ProteinP0CG47 (Uniprot-TrEMBL)
UBB(77-152) ProteinP0CG47 (Uniprot-TrEMBL)
UBC(1-76) ProteinP0CG48 (Uniprot-TrEMBL)
UBC(153-228) ProteinP0CG48 (Uniprot-TrEMBL)
UBC(229-304) ProteinP0CG48 (Uniprot-TrEMBL)
UBC(305-380) ProteinP0CG48 (Uniprot-TrEMBL)
UBC(381-456) ProteinP0CG48 (Uniprot-TrEMBL)
UBC(457-532) ProteinP0CG48 (Uniprot-TrEMBL)
UBC(533-608) ProteinP0CG48 (Uniprot-TrEMBL)
UBC(609-684) ProteinP0CG48 (Uniprot-TrEMBL)
UBC(77-152) ProteinP0CG48 (Uniprot-TrEMBL)
UBE2C ProteinO00762 (Uniprot-TrEMBL)
UBE2D1 ProteinP51668 (Uniprot-TrEMBL)
UBE2E1 ProteinP51965 (Uniprot-TrEMBL)
Ub-EHMT1:Ub-EHMT2:Cdh1:p-APC/CComplexR-HSA-3788739 (Reactome)
UbComplexR-HSA-68524 (Reactome)
p-2S-JUN:p-2S,2T-FOS:IGFBP7 GeneComplexR-HSA-3797203 (Reactome)
p-2S-JUN:p-2S,2T-FOS:IL1A geneComplexR-HSA-4568738 (Reactome)
p-2S-cJUN:p-2S,2T-cFOSComplexR-HSA-450327 (Reactome)
p-4S,T231,T365-RPS6KA3 ProteinP51812 (Uniprot-TrEMBL)
p-4S,T356,T570-RPS6KA2 ProteinQ15349 (Uniprot-TrEMBL)
p-4S,T359,T573-RPS6KA1 ProteinQ15418 (Uniprot-TrEMBL)
p-ERK1/2/5ComplexR-HSA-199878 (Reactome)
p-FZR1 ProteinQ9UM11 (Uniprot-TrEMBL)
p-S63,S73-JUN ProteinP05412 (Uniprot-TrEMBL)
p-T,Y MAPK dimersComplexR-HSA-198701 (Reactome)
p-T160-CDK2 ProteinP24941 (Uniprot-TrEMBL)
p-T185,Y187-MAPK1 ProteinP28482 (Uniprot-TrEMBL)
p-T202,Y204-MAPK3 ProteinP27361 (Uniprot-TrEMBL)
p-T218,Y220-MAPK7 ProteinQ13164 (Uniprot-TrEMBL)
p-T235, S321-CEBPB ProteinP17676 (Uniprot-TrEMBL)
p-T235, S321-CEBPBProteinP17676 (Uniprot-TrEMBL)
p-T235,S321-CEBPB homodimerComplexR-HSA-3857334 (Reactome)
p-T235,S321-CEBPB:CDKN2B GeneComplexR-HSA-3857347 (Reactome)
p-T235,S321-CEBPB:NF-kB:IL6 geneComplexR-HSA-3857324 (Reactome)
p-T235,S321-CEBPB:NF-kB:IL8 GeneComplexR-HSA-3857319 (Reactome)
p-T235-CEBPBProteinP17676 (Uniprot-TrEMBL)
p-T325,T331,S362,S374-FOS ProteinP01100 (Uniprot-TrEMBL)
p-Y705-STAT3 ProteinP40763 (Uniprot-TrEMBL)
p-Y705-STAT3 dimerComplexR-HSA-1112525 (Reactome)
p16-INK4a ProteinP42771 (Uniprot-TrEMBL)

Annotated Interactions

View all...
SourceTargetTypeDatabase referenceComment
2xMyri-IL1AArrowR-HSA-4568740 (Reactome)
ADPArrowR-HSA-198746 (Reactome)
ADPArrowR-HSA-3788705 (Reactome)
ADPArrowR-HSA-3857328 (Reactome)
ADPArrowR-HSA-3857329 (Reactome)
ATPR-HSA-198746 (Reactome)
ATPR-HSA-3788705 (Reactome)
ATPR-HSA-3857328 (Reactome)
ATPR-HSA-3857329 (Reactome)
AdoHcyArrowR-HSA-3788745 (Reactome)
AdoHcyArrowR-HSA-3788748 (Reactome)
AdoMetR-HSA-3788745 (Reactome)
AdoMetR-HSA-3788748 (Reactome)
ArrowR-HSA-3790130 (Reactome)
ArrowR-HSA-3790137 (Reactome)
CCNA:p-T160-CDK2R-HSA-3788708 (Reactome)
CDK4,CDK6:INK4ArrowR-HSA-182594 (Reactome)
CDK4,CDK6R-HSA-182594 (Reactome)
CDKN2B geneR-HSA-3857345 (Reactome)
CDKN2B geneR-HSA-3857348 (Reactome)
CDKN2BArrowR-HSA-3857348 (Reactome)
CEBPB geneR-HSA-3858387 (Reactome)
CEBPBArrowR-HSA-3858387 (Reactome)
CEBPBR-HSA-3857329 (Reactome)
Cdh1:phospho-APC/C complexR-HSA-3788708 (Reactome)
Cdh1:phospho-APC/C complexR-HSA-3788725 (Reactome)
Cyclin

A:Cdk2:p21/p27

complex
TBarR-HSA-3788705 (Reactome)
Cyclin

A:Cdk2:p21/p27

complex
TBarR-HSA-3788708 (Reactome)
Cyclin

A:phospho-Cdk(Thr

160):Cdh1:phosho-APC/C complex
ArrowR-HSA-3788708 (Reactome)
Cyclin

A:phospho-Cdk(Thr

160):Cdh1:phosho-APC/C complex
R-HSA-3788705 (Reactome)
Cyclin

A:phospho-Cdk(Thr

160):Cdh1:phosho-APC/C complex
mim-catalysisR-HSA-3788705 (Reactome)
Cyclin

A:phospho-Cdk2(Thr

160):phospho-Cdh1:phospho-APC/C complex
ArrowR-HSA-3788705 (Reactome)
EHMT1:EHMT2:Cdh1:p-APC/CArrowR-HSA-3788725 (Reactome)
EHMT1:EHMT2:Cdh1:p-APC/CR-HSA-3788724 (Reactome)
EHMT1:EHMT2:Cdh1:p-APC/Cmim-catalysisR-HSA-3788724 (Reactome)
EHMT1:EHMT2R-HSA-3788725 (Reactome)
EHMT1:EHMT2TBarR-HSA-3790130 (Reactome)
EHMT1:EHMT2TBarR-HSA-3790137 (Reactome)
EHMT1:EHMT2mim-catalysisR-HSA-3788745 (Reactome)
EHMT1:EHMT2mim-catalysisR-HSA-3788748 (Reactome)
IGFBP7 geneR-HSA-3797196 (Reactome)
IGFBP7 geneR-HSA-3797202 (Reactome)
IGFBP7ArrowR-HSA-3797202 (Reactome)
IL1A gene