Senescence-associated secretory phenotype (SASP) (Homo sapiens)

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2, 8, 10, 19, 26...10819988, 10, 15, 24, 38...8, 159, 14, 16, 39, 65...2, 8, 10, 15, 24...1064, 27, 53, 838982, 8, 9856, 8510, 38, 63, 82, 89...9, 14, 16, 39, 65...561910, 26, 38, 56, 63...56567, 5625, 56nucleoplasmcytosolANAPC4 CDC23 ANAPC4 CDC26 ADPUBE2E1 NFKB1(1-433) CCNA:p-T160-CDK2Me2K-10-HIST2H3A p-T235,S321-CEBPBhomodimerANAPC1 ANAPC10 RELA p-T325,T331,S362,S374-FOS HIST1H4 UBE2D1 H3F3A Ribosomal protein S6kinaseHIST2H3A CDC23 IL8 Gene ATPCDKN2D ANAPC11 Me2K10-HIST1H3A CDC26 RELA p16-INK4a ATPCDC23 UBE2C ANAPC4 EHMT1 HIST2H3A EHMT1 UBC(1-76) ANAPC4 IGFBP7 GeneINK4AANAPC1 ANAPC7 HIST1H4 ANAPC2 ANAPC11 HIST1H3A p-T325,T331,S362,S374-FOS UBE2C ANAPC5 UBE2D1 DNA Damage/TelomereStress InducedSenescenceHIST1H4 CEBPB GeneUBE2E1 ANAPC5 p-T235, S321-CEBPB UBE2D1 IL6 Gene Me2K-10-H3F3A Cdk4/6:INK4A complexIL6ubiquitinIL1A GeneIL6 Gene:NucleosomeANAPC1 CDKN2B gene EHMT2 p-Y705-STAT3 HIST2H3A 2xMyri-IL1AUBE2C HIST1H4 HIST1H3A Cdk4/6Interleukin-1signalingCDC16 CDK4 Oncogene InducedSenescenceUBE2C UBC(457-532) ANAPC1 p-T160-CDK2 ATPCDKN2C ANAPC1 HIST1H4 RPS27A(1-76) CDKN1B UBA52(1-76) IL8 Gene:NucleosomeANAPC2 p-S63,S73-JUN IGFBP7UBE2D1 FZR1 IL6 Gene Ub-EHMT1:Ub-EHMT2:Cdh1:p-APC/CCDC16 CDC16 p(Y705)-STAT3 dimerRELA ANAPC10 CDC23 p-2S-JUN:p-2S,2T-FOS:IL1A Genep-2S-cJUN:p-2S,2T-cFOSCDC27 p-ERK1/2/5CDC23 p-T185,Y187-MAPK1 ANAPC7 UBC(381-456) p-T235, S321-CEBPBCyclinA:phospho-Cdk(Thr160):Cdh1:phosho-APC/C complexUBC(153-228) CDK2 Oxidative StressInduced SenescenceUBC(533-608) EHMT1:EHMT2:Cdh1:p-APC/CCyclinA:phospho-Cdk2(Thr160):phospho-Cdh1:phospho-APC/C complexCDC27 ATPCdh1:phospho-APC/CcomplexCDKN1A UBC(305-380) UBB(1-76) IL8 Gene EHMT2 CDK6 HIST1H4 p-T235-CEBPBUBE2C AdoMetp-T160-CDK2 UBE2E1 CEBPBANAPC4 ANAPC5 IL6Gene:Nucleosome-H3K9Me2IL8 Gene p-T235,S321-CEBPB:CDKN2B GeneCyclinA:Cdk2:p21/p27complexEHMT2 ANAPC7 Me2K-10-HIST2H3A ANAPC11 UBE2E1 UBE2E1 p-FZR1 CDC27 CDC16 ANAPC5 ANAPC10 CDC27 H3F3A ADPIL8UBC(229-304) HIST2H3A p-T202,Y204-MAPK3 Phospho-Ribosomalprotein S6 kinaseHIST1H3A EHMT1:EHMT2ANAPC5 p-T235, S321-CEBPB p-S63,S73-JUN IGFBP7 Gene ANAPC10 UBB(77-152) p-2S-JUN:p-2S,2T-FOS:IGFBP7 GeneIL6 Gene Me2K10-HIST1H3A ANAPC2 ANAPC2 UBB(153-228) FZR1 IL1A Gene CDC16 NFKB1(1-433) IL8Gene:Nucleosome-H3K9Me2p-T235,S321-CEBPB:NF-kB:IL6 Gene:NucleosomeANAPC11 FZR1 CDC26 CDKN2BADPInterleukin-6signalingp-T235, S321-CEBPB FZR1 p-T,Y MAPK dimersUBC(609-684) ADPHIST1H3A p-T235,S321-CEBPB:NF-kB:IL8 Gene:NucleosomeCDKN2B H3F3A p-S63,S73-JUN p-T160-CDK2 CDC26 CDKN2B geneANAPC10 ANAPC7 p-T235, S321-CEBPB ANAPC2 NF-kB complexUBC(77-152) AdoHcyH3F3A CDC27 p-T325,T331,S362,S374-FOS CDC26 EHMT1 Me2K-10-H3F3A UBE2D1 NFKB1(1-433) ANAPC7 ANAPC11 75698565535, 44, 46, 53, 62...8, 15193, 13, 17, 18, 20...23, 74111, 5, 6, 12, 21...98


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. Source:Reactome.</div>

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  92. Coppé JP, Patil CK, Rodier F, Sun Y, Muñoz DP, Goldstein J, Nelson PS, Desprez PY, Campisi J.; ''Senescence-associated secretory phenotypes reveal cell-nonautonomous functions of oncogenic RAS and the p53 tumor suppressor.''; PubMed Europe PMC Scholia
  93. Smogorzewska A, van Steensel B, Bianchi A, Oelmann S, Schaefer MR, Schnapp G, de Lange T.; ''Control of human telomere length by TRF1 and TRF2.''; PubMed Europe PMC Scholia
  94. Karlseder J, Broccoli D, Dai Y, Hardy S, de Lange T.; ''p53- and ATM-dependent apoptosis induced by telomeres lacking TRF2.''; PubMed Europe PMC Scholia
  95. 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 Scholia
  96. Bembenek J, Yu H.; ''Regulation of the anaphase-promoting complex by the dual specificity phosphatase human Cdc14a.''; PubMed Europe PMC Scholia
  97. Samatar AA, Poulikakos PI.; ''Targeting RAS-ERK signalling in cancer: promises and challenges.''; PubMed Europe PMC Scholia
  98. Rogers CD, Archer TC, Cunningham DD, Grammer TC, Casey EM.; ''Sox3 expression is maintained by FGF signaling and restricted to the neural plate by Vent proteins in the Xenopus embryo.''; PubMed Europe PMC Scholia
  99. Wu Y, Xiao S, Zhu XD.; ''MRE11-RAD50-NBS1 and ATM function as co-mediators of TRF1 in telomere length control.''; PubMed Europe PMC Scholia
  100. Ohtani N, Zebedee Z, Huot TJ, Stinson JA, Sugimoto M, Ohashi Y, Sharrocks AD, Peters G, Hara E.; ''Opposing effects of Ets and Id proteins on p16INK4a expression during cellular senescence.''; PubMed Europe PMC Scholia
  101. Roux PP, Richards SA, Blenis J.; ''Phosphorylation of p90 ribosomal S6 kinase (RSK) regulates extracellular signal-regulated kinase docking and RSK activity.''; PubMed Europe PMC Scholia
  102. White A, Pargellis CA, Studts JM, Werneburg BG, Farmer BT.; ''Molecular basis of MAPK-activated protein kinase 2:p38 assembly.''; PubMed Europe PMC Scholia
  103. Stein B, Baldwin AS.; ''Distinct mechanisms for regulation of the interleukin-8 gene involve synergism and cooperativity between C/EBP and NF-kappa B.''; PubMed Europe PMC Scholia
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  105. Erickson S, Sangfelt O, Heyman M, Castro J, Einhorn S, Grandér D.; ''Involvement of the Ink4 proteins p16 and p15 in T-lymphocyte senescence.''; PubMed Europe PMC Scholia
  106. Wajapeyee N, Serra RW, Zhu X, Mahalingam M, Green MR.; ''Oncogenic BRAF induces senescence and apoptosis through pathways mediated by the secreted protein IGFBP7.''; PubMed Europe PMC Scholia
  107. Dinarello CA.; ''Immunological and inflammatory functions of the interleukin-1 family.''; PubMed Europe PMC Scholia
  108. 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 Scholia
  109. Prior IA, Lewis PD, Mattos C.; ''A comprehensive survey of Ras mutations in cancer.''; PubMed Europe PMC Scholia
  110. Lukas C, Sørensen CS, Kramer E, Santoni-Rugiu E, Lindeneg C, Peters JM, Bartek J, Lukas J.; ''Accumulation of cyclin B1 requires E2F and cyclin-A-dependent rearrangement of the anaphase-promoting complex.''; PubMed Europe PMC Scholia
  111. Orjalo AV, Bhaumik D, Gengler BK, Scott GK, Campisi J.; ''Cell surface-bound IL-1alpha is an upstream regulator of the senescence-associated IL-6/IL-8 cytokine network.''; PubMed Europe PMC Scholia
  112. Khanna KK, Keating KE, Kozlov S, Scott S, Gatei M, Hobson K, Taya Y, Gabrielli B, Chan D, Lees-Miller SP, Lavin MF.; ''ATM associates with and phosphorylates p53: mapping the region of interaction.''; PubMed Europe PMC Scholia
  113. Baron VT, Pio R, Jia Z, Mercola D.; ''Early Growth Response 3 regulates genes of inflammation and directly activates IL6 and IL8 expression in prostate cancer.''; PubMed Europe PMC Scholia
  114. Murakami Y, Watari K, Shibata T, Uba M, Ureshino H, Kawahara A, Abe H, Izumi H, Mukaida N, Kuwano M, Ono M.; ''N-myc downstream-regulated gene 1 promotes tumor inflammatory angiogenesis through JNK activation and autocrine loop of interleukin-1α by human gastric cancer cells.''; PubMed Europe PMC Scholia
  115. Garbers C, Hermanns HM, Schaper F, Müller-Newen G, Grötzinger J, Rose-John S, Scheller J.; ''Plasticity and cross-talk of interleukin 6-type cytokines.''; PubMed Europe PMC Scholia
  116. Bracken AP, Kleine-Kohlbrecher D, Dietrich N, Pasini D, Gargiulo G, Beekman C, Theilgaard-Mönch K, Minucci S, Porse BT, Marine JC, Hansen KH, Helin K.; ''The Polycomb group proteins bind throughout the INK4A-ARF locus and are disassociated in senescent cells.''; PubMed Europe PMC Scholia
  117. Taga T.; ''Gp130, a shared signal transducing receptor component for hematopoietic and neuropoietic cytokines.''; PubMed Europe PMC Scholia
  118. Kishimoto T, Akira S, Narazaki M, Taga T.; ''Interleukin-6 family of cytokines and gp130.''; PubMed Europe PMC Scholia
  119. Burleson FG, Simeonova PP, Germolec DR, Luster MI.; ''Dermatotoxic chemical stimulate of c-jun and c-fos transcription and AP-1 DNA binding in human keratinocytes.''; PubMed Europe PMC Scholia
  120. Vijayachandra K, Lee J, Glick AB.; ''Smad3 regulates senescence and malignant conversion in a mouse multistage skin carcinogenesis model.''; PubMed Europe PMC Scholia
  121. Hannon GJ, Beach D.; ''p15INK4B is a potential effector of TGF-beta-induced cell cycle arrest.''; PubMed Europe PMC Scholia
  122. Nakashima K, Taga T.; ''gp130 and the IL-6 family of cytokines: signaling mechanisms and thrombopoietic activities.''; PubMed Europe PMC Scholia
  123. Niu J, Li Z, Peng B, Chiao PJ.; ''Identification of an autoregulatory feedback pathway involving interleukin-1alpha in induction of constitutive NF-kappaB activation in pancreatic cancer cells.''; PubMed Europe PMC Scholia
  124. Murphy LO, Smith S, Chen RH, Fingar DC, Blenis J.; ''Molecular interpretation of ERK signal duration by immediate early gene products.''; PubMed Europe PMC Scholia
  125. Clifton AD, Young PR, Cohen P.; ''A comparison of the substrate specificity of MAPKAP kinase-2 and MAPKAP kinase-3 and their activation by cytokines and cellular stress.''; PubMed Europe PMC Scholia
  126. 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 Scholia
  127. Le Gallic L, Virgilio L, Cohen P, Biteau B, Mavrothalassitis G.; ''ERF nuclear shuttling, a continuous monitor of Erk activity that links it to cell cycle progression.''; PubMed Europe PMC Scholia
  128. Lukas SM, Kroe RR, Wildeson J, Peet GW, Frego L, Davidson W, Ingraham RH, Pargellis CA, Labadia ME, Werneburg BG.; ''Catalysis and function of the p38 alpha.MK2a signaling complex.''; PubMed Europe PMC Scholia
  129. Maertens O, Cichowski K.; ''An expanding role for RAS GTPase activating proteins (RAS GAPs) in cancer.''; PubMed Europe PMC Scholia
  130. Raingeaud J, Whitmarsh AJ, Barrett T, Dérijard B, Davis RJ.; ''MKK3- and MKK6-regulated gene expression is mediated by the p38 mitogen-activated protein kinase signal transduction pathway.''; PubMed Europe PMC Scholia
  131. Harper JW, Adami GR, Wei N, Keyomarsi K, Elledge SJ.; ''The p21 Cdk-interacting protein Cip1 is a potent inhibitor of G1 cyclin-dependent kinases.''; PubMed Europe PMC Scholia
  132. Shimizu H, Mitomo K, Watanabe T, Okamoto S, Yamamoto K.; ''Involvement of a NF-kappa B-like transcription factor in the activation of the interleukin-6 gene by inflammatory lymphokines.''; PubMed Europe PMC Scholia
  133. 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 Scholia
  134. Mizukami Y, Yoshioka K, Morimoto S, Yoshida Ki.; ''A novel mechanism of JNK1 activation. Nuclear translocation and activation of JNK1 during ischemia and reperfusion.''; PubMed Europe PMC Scholia
  135. Zhong YF, Holland PW.; ''The dynamics of vertebrate homeobox gene evolution: gain and loss of genes in mouse and human lineages.''; PubMed Europe PMC Scholia
  136. 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 Scholia
  137. Trinh BQ, Barengo N, Kim SB, Lee JS, Zweidler-McKay PA, Naora H.; ''The homeobox gene DLX4 regulates erythro-megakaryocytic differentiation by stimulating IL-1β and NF-κB signaling.''; PubMed Europe PMC Scholia
  138. Glover JN, Harrison SC.; ''Crystal structure of the heterodimeric bZIP transcription factor c-Fos-c-Jun bound to DNA.''; PubMed Europe PMC Scholia
  139. Lin TY, Cheng YC, Yang HC, Lin WC, Wang CC, Lai PL, Shieh SY.; ''Loss of the candidate tumor suppressor BTG3 triggers acute cellular senescence via the ERK-JMJD3-p16(INK4a) signaling axis.''; PubMed Europe PMC Scholia
  140. Wu X, Gao H, Bleday R, Zhu Z.; ''Homeobox transcription factor VentX regulates differentiation and maturation of human dendritic cells.''; PubMed Europe PMC Scholia
  141. Young AR, Narita M.; ''SASP reflects senescence.''; PubMed Europe PMC Scholia
  142. Nelson ML, Kang HS, Lee GM, Blaszczak AG, Lau DK, McIntosh LP, Graves BJ.; ''Ras signaling requires dynamic properties of Ets1 for phosphorylation-enhanced binding to coactivator CBP.''; PubMed Europe PMC Scholia
  143. Moiseeva O, Bourdeau V, Roux A, Deschênes-Simard X, Ferbeyre G.; ''Mitochondrial dysfunction contributes to oncogene-induced senescence.''; PubMed Europe PMC Scholia
  144. Wu X, Bayle JH, Olson D, Levine AJ.; ''The p53-mdm-2 autoregulatory feedback loop.''; PubMed Europe PMC Scholia
  145. Seidel JJ, Graves BJ.; ''An ERK2 docking site in the Pointed domain distinguishes a subset of ETS transcription factors.''; PubMed Europe PMC Scholia
  146. Le Y, Gao H, Bleday R, Zhu Z.; ''The homeobox protein VentX reverts immune suppression in the tumor microenvironment.''; PubMed Europe PMC Scholia
  147. Voncken JW, Niessen H, Neufeld B, Rennefahrt U, Dahlmans V, Kubben N, Holzer B, Ludwig S, Rapp UR.; ''MAPKAP kinase 3pK phosphorylates and regulates chromatin association of the polycomb group protein Bmi1.''; PubMed Europe PMC Scholia
  148. Matsusaka T, Fujikawa K, Nishio Y, Mukaida N, Matsushima K, Kishimoto T, Akira S.; ''Transcription factors NF-IL6 and NF-kappa B synergistically activate transcription of the inflammatory cytokines, interleukin 6 and interleukin 8.''; PubMed Europe PMC Scholia
  149. New L, Jiang Y, Zhao M, Liu K, Zhu W, Flood LJ, Kato Y, Parry GC, Han J.; ''PRAK, a novel protein kinase regulated by the p38 MAP kinase.''; PubMed Europe PMC Scholia
  150. Kishimoto T.; ''IL-6: from its discovery to clinical applications.''; PubMed Europe PMC Scholia
  151. Banin S, Moyal L, Shieh S, Taya Y, Anderson CW, Chessa L, Smorodinsky NI, Prives C, Reiss Y, Shiloh Y, Ziv Y.; ''Enhanced phosphorylation of p53 by ATM in response to DNA damage.''; PubMed Europe PMC Scholia

History

View all...
CompareRevisionActionTimeUserComment
129524view01:02, 9 May 2024EweitzModified title
114857view16:36, 25 January 2021ReactomeTeamReactome version 75
113303view11:37, 2 November 2020ReactomeTeamReactome version 74
112515view15:47, 9 October 2020ReactomeTeamReactome version 73
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)
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)
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)
CDK6 ProteinQ00534 (Uniprot-TrEMBL)
CDKN1A ProteinP38936 (Uniprot-TrEMBL)
CDKN1B ProteinP46527 (Uniprot-TrEMBL)
CDKN2B ProteinP42772 (Uniprot-TrEMBL)
CDKN2B gene ProteinENSG00000147883 (ENSEMBL)
CDKN2B geneENSG00000147883 (ENSEMBL)
CDKN2BProteinP42772 (Uniprot-TrEMBL)
CDKN2C ProteinP42773 (Uniprot-TrEMBL)
CDKN2D ProteinP55273 (Uniprot-TrEMBL)
CEBPB GeneENSG00000172216 (ENSEMBL)
CEBPBProteinP17676 (Uniprot-TrEMBL)
Cdh1:phospho-APC/C complexComplexR-HSA-174250 (Reactome)
Cdk4/6:INK4A complexComplexR-HSA-182579 (Reactome)
Cdk4/6ProteinR-HSA-69209 (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)
H3F3A ProteinP84243 (Uniprot-TrEMBL)
HIST1H3A ProteinP68431 (Uniprot-TrEMBL)
HIST1H4 ProteinP62805 (Uniprot-TrEMBL)
HIST2H3A ProteinQ71DI3 (Uniprot-TrEMBL)
IGFBP7 Gene ProteinENSG00000163453 (ENSEMBL)
IGFBP7 GeneENSG00000163453 (ENSEMBL)
IGFBP7ProteinQ16270 (Uniprot-TrEMBL)
IL1A Gene ProteinENSG00000115008 (ENSEMBL)
IL1A GeneENSG00000115008 (ENSEMBL)
IL6 Gene:Nucleosome-H3K9Me2ComplexR-HSA-3788744 (Reactome)
IL6 Gene ProteinENSG00000136244 (ENSEMBL)
IL6 Gene:NucleosomeComplexR-HSA-3788741 (Reactome)
IL6ProteinP05231 (Uniprot-TrEMBL)
IL8 Gene:Nucleosome-H3K9Me2ComplexR-HSA-3788746 (Reactome)
IL8 Gene ProteinENSG00000169429 (ENSEMBL)
IL8 Gene:NucleosomeComplexR-HSA-3788743 (Reactome)
IL8ProteinP10145 (Uniprot-TrEMBL)
INK4AProteinR-HSA-182588 (Reactome)
Interleukin-1 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 signalingPathwayR-HSA-1059683 (Reactome) Interleukin-6 (IL-6) is a pleiotropic cytokine with roles in processes including immune regulation, hematopoiesis, inflammation, oncogenesis, metabolic control and sleep. It is the founding member of a family of IL-6-related cytokines such as IL-11, IL-27 leukemia inhibitory factor (LIF), cilliary neurotrophic factor (CNTF) and oncostatin M.

The IL-6 receptor (IL6R) consists of an alpha subunit that specifically binds IL-6 and a beta subunit, IL6RB or gp130, which is the signaling component of all the receptors for cytokines related to IL-6. 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 IL-6 whereas the membrane bound receptor governs regenerative and anti-inflammatory IL-6 activities

IL6R signal transduction is mediated by two pathways:the JAK-STAT (Janus family tyrosine kinase-signal transducer and activator of transcription) pathway and the Ras-MAPK (mitogen-activated protein kinase) pathway. Negative regulators of IL-6 signaling include SOCS (suppressor of cytokine signals) and SHP2. Within the last few years different antibodies have been developed to inhibit IL-6 activity, and the first such antibodies have been introduced into the clinic 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. 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.

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 kinaseProteinR-HSA-199849 (Reactome)
RELA ProteinQ04206 (Uniprot-TrEMBL)
RPS27A(1-76) ProteinP62979 (Uniprot-TrEMBL)
Ribosomal protein S6 kinaseProteinR-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)
p(Y705)-STAT3 dimerComplexR-HSA-1112525 (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-ERK1/2/5R-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-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 Gene:NucleosomeComplexR-HSA-3857324 (Reactome)
p-T235,S321-CEBPB:NF-kB:IL8 Gene:NucleosomeComplexR-HSA-3857319 (Reactome)
p-T235-CEBPBProteinP17676 (Uniprot-TrEMBL)
p-T325,T331,S362,S374-FOS ProteinP01100 (Uniprot-TrEMBL)
p-Y705-STAT3 ProteinP40763 (Uniprot-TrEMBL)
p16-INK4a ProteinP42771 (Uniprot-TrEMBL)
ubiquitinProteinR-HSA-68524 (Reactome)

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)
CCNA:p-T160-CDK2R-HSA-3788708 (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)
Cdk4/6:INK4A complexArrowR-HSA-182594 (Reactome)
Cdk4/6R-HSA-182594 (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: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 GeneR-HSA-4568737 (Reactome)
IL1A GeneR-HSA-4568740 (Reactome)
IL6 Gene:Nucleosome-H3K9Me2ArrowR-HSA-3788748 (Reactome)
IL6 Gene:Nucleosome-H3K9Me2TBarR-HSA-3790130 (Reactome)
IL6 Gene:NucleosomeR-HSA-3788748 (Reactome)
IL6 Gene:NucleosomeR-HSA-3790130 (Reactome)
IL6 Gene:NucleosomeR-HSA-3857305 (Reactome)
IL6ArrowR-HSA-3790130 (Reactome)
IL8 Gene:Nucleosome-H3K9Me2ArrowR-HSA-3788745 (Reactome)
IL8 Gene:Nucleosome-H3K9Me2TBarR-HSA-3790137 (Reactome)
IL8 Gene:NucleosomeR-HSA-3788745 (Reactome)
IL8 Gene:NucleosomeR-HSA-3790137 (Reactome)
IL8 Gene:NucleosomeR-HSA-3857308 (Reactome)
IL8ArrowR-HSA-3790137 (Reactome)
INK4AR-HSA-182594 (Reactome)
NF-kB complexR-HSA-3857305 (Reactome)
NF-kB complexR-HSA-3857308 (Reactome)
Phospho-Ribosomal protein S6 kinaseArrowR-HSA-198746 (Reactome)
Phospho-Ribosomal protein S6 kinasemim-catalysisR-HSA-3857328 (Reactome)
R-HSA-182594 (Reactome) Prior to mitogen activation, the inhibitory proteins, INK4 (p15, p16, p18, and p19) associate with the catalytic domain of free CDK4/6, preventing its association with cyclins, and thus its activation.
R-HSA-198746 (Reactome) The p90 ribosomal S6 kinases (RSK1-4) comprise a family of serine/threonine kinases that lie at the terminus of the ERK pathway. RSK family members are unusual among serine/threonine kinases in that they contain two distinct kinase domains, both of which are catalytically functional . The C-terminal kinase domain is believed to be involved in autophosphorylation, a critical step in RSK activation, whereas the N-terminal kinase domain, which is homologous to members of the AGC superfamily of kinases, is responsible for the phosphorylation of all known exogenous substrates of RSK.
RSKs can be activated by the ERKs (ERK1, 2, 5) in the cytoplasm as well as in the nucleus, they both have cytoplasmic and nuclear substrates, and they are able to move from nucleus to cytoplasm. Efficient RSK activation by ERKs requires its interaction through a docking site located near the RSK C terminus. The mechanism of RSK activation has been studied mainly with regard to ERK1 and ERK2. RSK activation leads to the phosphorylation of four essential residues Ser239, Ser381, Ser398, and Thr590, and two additional sites, Thr377 and Ser749 (the amino acid numbering refers to RSK1). ERK is thought to play at least two roles in RSK1 activation. First, activated ERK phosphorylates RSK1 on Thr590, and possibly on Thr377 and Ser381, and second, ERK brings RSK1 into close proximity to membrane-associated kinases that may phosphorylate RSK1 on Ser381 and Ser398.
Moreover, RSKs and ERK1/2 form a complex that transiently dissociates upon growth factor signalling. Complex dissociation requires phosphorylation of RSK1 serine 749, a growth factor regulated phosphorylation site located near the ERK docking site. Serine 749 is phosphorylated by the N-terminal kinase domain of RSK1 itself. ERK1/2 docking to RSK2 and RSK3 is also regulated in a similar way. The length of RSK activation following growth factor stimulation depends on the duration of the RSK/ERK complex, which, in turn, differs among the different RSK isoforms. RSK1 and RSK2 readily dissociate from ERK1/2 following growth factor stimulation stimulation, but RSK3 remains associated with active ERK1/2 longer, and also remains active longer than RSK1 and RSK2.

R-HSA-3788705 (Reactome) At the G1/S transition, the Cdh1 (FZR1) subunit of the APC/C:Cdh1 complex is phosphorylated by Cyclin A:Cdk2 (CCNA:CDK2) and dissociates from APC/C. This inactivates APC/C and permits the accumulation of cell cycle proteins required for DNA synthesis and entry into mitosis (Lukas et al. 1999). Activation of the ATM kinase by DNA damage in the form of double strand breaks results in TP53-mediated induction of CDKN1A (p21) expression. CDKN1A binds CCNA:CDK2 complex and prevents it from phosphorylating Cdh1 (Takahashi et al. 2012).
R-HSA-3788708 (Reactome) Cyclin A-Cdk2 (CCNA:CDK2) prevents unscheduled APC reactivation during S phase by binding and subsequently phosphorylating FZR1 (Cdh1). Phosphorylation-dependent dissociation of the Cdh1-activating subunit inhibits the APC/C (Sorensen et al. 2001). DNA damage activates ATM kinase, resulting in TP53-mediated induction of CDKN1A (p21) expression. CDKN1A binds CCNA:CDK2 complex and prevents its association with Cdh1 (Takahashi et al. 2012).
R-HSA-3788724 (Reactome) Cdh1:APC/C complex, stabilized by the DNA damage-induced ATM-TP53-CDKN1A axis, ubiquitinates EHMT1 (GLP) and EHMT2 (G9a) histone methyltransferases, targeting them for degradation (Takahashi et al. 2012).
R-HSA-3788725 (Reactome) Cdh1 (FZR1) is able to bind both G9a (EHMT2) and GLP (EHMT1) (Takahashi et al. 2012). EHMT1 and EHMT2 histone methyltransferases were shown to function as a heterodimer in vivo (Tachibana et al. 2005).
R-HSA-3788745 (Reactome) EHMT1 (GLP) and EHMT2 (G9a) histone methyltransferases dimethylate histone H3 (HIST1H3A) on lysine residue 10, creating an H3K9Me2 mark on nucleosomes associated with the IL8 promoter (Takahashi et al. 2012).
R-HSA-3788748 (Reactome) EHMT1 (GLP) and EHMT2 (G9a) histone methyltransferases dimethylate histone H3 (HIST1H3A) on lysine residue 10, creating an H3K9Me2 mark on nucleosomes associated with the IL6 promoter (Takahashi et al. 2012).
R-HSA-3790130 (Reactome) Methylation of the IL6 promoter by EHMT1:EHMT2 (GLP:G9a) histone methyltransferases inhibits IL6 transcription, while Cdh1:APC/C-mediated degradation of EHTM1:EHTM2 downstream of the ATM-TP53-CDKN1A axis stimulates IL6 transcription (Takahashi et al. 2012). Oncogenic RAS signaling stimulates activation of the CEBPB transcription factor (C/EBP-beta) which binds IL6 promoter and stimulates IL6 transcription (Kuilman et al. 2008, Lee et al. 2010). NF kappa B transcription factor is also activated in senescent cells (Chien et al. 2011) through interleukin-1-alpha (IL1A) signaling (Jimi et al. 1996, Hartupee et al. 2008, Orjalo et al. 2009), and it cooperates with CEBPB in the activation of IL6 transcription (Shimizu et al. 1990, Libermann and Baltimore 1990, Matsusaka et al. 1993, Acosta et al. 2008). Autocrine IL6 signaling stimulates CEBPB expression (Kuilman et al. 2008), creating a positive feedback loop. STAT3, activated by IL6 signaling cascade is necessary for CEBPB transcription, but the direct binding of STAT3 to the CEBPB promoter has not been demonstrated (Niehof et al. 2001).
R-HSA-3790137 (Reactome) Methylation of the IL8 promoter by EHMT1:EHMT2 (GLP:G9a) histone methyltransferases inhibits IL8 transcription, while Cdh1:APC/C-mediated degradation of EHTM1:EHTM2 downstream of the ATM-TP53-CDKN1A axis stimulates IL8 transcription (Takahashi et al. 2012). CEBPB transcription factor, activated by oncogenic RAS signaling, binds IL8 promoter and stimulates IL8 transcription (Kuilman et al. 2008). The NF-kappa-B transcription factor is also activated in senescent cells (Chien et al. 2011) through interleukin-1-alpha (IL1A) signaling (Jimi et al. 1996, Hartupee et al. 2008, Orjalo et al. 2009), and it cooperates with CEBPB in the activation of IL8 transcription (Kunsch and Rosen 1993, Stein and Baldwin 1993, Matsusaka et al. 1993, Acosta et al. 2008).
R-HSA-3797196 (Reactome) FOS:JUN (AP-1) transcription factor, formed in response to oncogenic RAF-MAPK signaling which also triggers oxidative stress, binds the promoter of IGFBP7 gene (Wajapeyee et al. 2008).
R-HSA-3797202 (Reactome) FOS:JUN (AP-1) transcription factor stimulates the transcription of IGFBP7 gene. IGFBP7 is a component of the senescence-associated secretory phenotype (SASP) and is secreted by senescent melanocytes in which the senescence is induced by the expression of oncogenic BRAF V600E. The BRAF V600E-mediated induction of IGFBP7 expression is AP-1 dependent. The conditioned medium harvested from BRAF V600E senescent melanocytes is able to inhibit cellular proliferation and induce senescence of naive melanocytes only when IGFBP7 is present in the medium (Wajapeyee et al. 2008).
R-HSA-3857305 (Reactome) RSK6A1/2/3-mediated phosphorylation of CEBPB downstream of activated RAS stimulates CEBPB homodimerization and DNA binding (Lee, Shuman et al. 2010) and, specifically, RAS-induced CEBPB activation stimulates CEBPB binding to the IL6 promoter (Kuilman et al. 2008; Lee, Shuman et al. 2010). RAS-activated CEBPB is able to recruit additional transcription activators, such as EP300, to the IL6 promoter (Lee, Miller et al. 2010). NFKB transcription complex, activated by interleukin-1-alpha (IL1A) signaling (Jimi et al. 1996, Hartupee et al. 2008, Orjalo et al. 2009), also binds the promoter of the IL6 gene (Shimizu et al. 1990, Libermann and Baltimore 1990) and cooperates with CEBPB in the activation of IL6 transcription (Matsusaka et al. 1993).
R-HSA-3857308 (Reactome) RAS-mediated activation of CEBPB (C/EBP-beta) stimulates CEBPB binding to the IL8 promoter (Kuilman et al. 2008). NFKB transcription complex, activated by interleukin-1-alpha (IL1A) signaling (Jimi et al. 1996, Hartupee et al. 2008, Orjalo et al. 2009), also binds the promoter of the IL8 gene (Kunsch and Rosen 1993) and cooperates with CEBPB in the activation of IL8 transcription (Matsusaka et al. 1993, Stein and Baldwin 1993).
R-HSA-3857328 (Reactome) Phosphorylation of CEBPB (C/EBP-beta) serine residue S321 by ERK1/2-activated RSK1, RSK2 or RSK3, downstream of activated RAS, is necessary for the relief of CEBPB autoinhibiton (Lee et al. 2010). Phosphorylation on other sites may also be involved in CEBPB activation.
R-HSA-3857329 (Reactome) Phosphorylation of CEBPB (C/EBP-beta) transcription factor on threonine residue T235 happens downstream of activated RAS, is mediated by MAPKs - likely MAPK3 (ERK1) and MAPK1 (ERK2), and positively affects CEBPB-mediated transcription of IL6 (Nakajima et al. 1993).
R-HSA-3857336 (Reactome) RSK1/2/3-mediated phosphorylation of CEBPB promotes the formation of CEBPB homodimers which are active as transcription factors (Lee, Miller et al. 2010; Lee, Shuman et al. 2010).
R-HSA-3857345 (Reactome) The CEBPB transcription factor, activated by oncogenic RAS signaling, binds the CDKN2B promoter (Kuilman et al. 2008).
R-HSA-3857348 (Reactome) Once bound to the CDKN2B promoter, CEBPB stimulates CKDN2B transcription, contributing to cell cycle arrest in oncogene induced senescence (Kuilman et al. 2008). In addition, since CEBPB expression is stimulated by IL6 signaling, with IL6 itself being a transcriptional target of CEBPB (Neihof et al. 2001, Kuilman et al. 2008, Lee et al. 2010), IL6-CEBPB-CDKN2B axis provides an autocrine SASP-mediated growth arrest mechanism.
R-HSA-3858387 (Reactome) STAT3, activated by IL6 signaling cascade, is necessary for CEBPB transcription, but direct binding of STAT3 to the CEBPB promoter has not been demonstrated (Niehof et al. 2001). As CEBPB activates IL6 transcription in response to oncogenic RAS signaling, and IL6 activates CEBPB transcription (Niehof et al. 2001, Kuilman et al. 2008, Lee et al. 2010), a positive feedback loop exists between CEBPB and IL6.
R-HSA-4568737 (Reactome) The promoter of the interleukin 1-alpha (IL1A) gene contains AP-1 binding sites which are occupied by the AP-1 (FOS:JUN) complex, resulting in the stimulation of IL1A transcription (Bailly et al. 1996 Alheim et al. 1996, Burleson et al. 1996, Huang et al. 1999, Niu et al. 2004, Moerman-Herzog and Barger 2012, Murakami et al. 2013).
R-HSA-4568740 (Reactome) The AP-1 complex (FOS:JUN) binds IL1A promoter and stimulates IL1A transcription (Bailly et al. 1996 Alheim et al. 1996, Burleson et al. 1996, Huang et al. 1999, Niu et al. 2004, Moerman-Herzog and Barger 2012, Murakami et al. 2013).
Ribosomal protein S6 kinaseR-HSA-198746 (Reactome)
Ub-EHMT1:Ub-EHMT2:Cdh1:p-APC/CArrowR-HSA-3788724 (Reactome)
Ub-EHMT1:Ub-EHMT2:Cdh1:p-APC/CArrowR-HSA-3790130 (Reactome)
Ub-EHMT1:Ub-EHMT2:Cdh1:p-APC/CArrowR-HSA-3790137 (Reactome)
p(Y705)-STAT3 dimerArrowR-HSA-3858387 (Reactome)
p-2S-JUN:p-2S,2T-FOS:IGFBP7 GeneArrowR-HSA-3797196 (Reactome)
p-2S-JUN:p-2S,2T-FOS:IGFBP7 GeneArrowR-HSA-3797202 (Reactome)
p-2S-JUN:p-2S,2T-FOS:IL1A GeneArrowR-HSA-4568737 (Reactome)
p-2S-JUN:p-2S,2T-FOS:IL1A GeneArrowR-HSA-4568740 (Reactome)
p-2S-cJUN:p-2S,2T-cFOSR-HSA-3797196 (Reactome)
p-2S-cJUN:p-2S,2T-cFOSR-HSA-4568737 (Reactome)
p-ERK1/2/5mim-catalysisR-HSA-198746 (Reactome)
p-T,Y MAPK dimersmim-catalysisR-HSA-3857329 (Reactome)
p-T235, S321-CEBPBArrowR-HSA-3857328 (Reactome)
p-T235, S321-CEBPBR-HSA-3857336 (Reactome)
p-T235,S321-CEBPB homodimerArrowR-HSA-3857336 (Reactome)
p-T235,S321-CEBPB homodimerR-HSA-3857305 (Reactome)
p-T235,S321-CEBPB homodimerR-HSA-3857308 (Reactome)
p-T235,S321-CEBPB homodimerR-HSA-3857345 (Reactome)
p-T235,S321-CEBPB:CDKN2B GeneArrowR-HSA-3857345 (Reactome)
p-T235,S321-CEBPB:CDKN2B GeneArrowR-HSA-3857348 (Reactome)
p-T235,S321-CEBPB:NF-kB:IL6 Gene:NucleosomeArrowR-HSA-3857305 (Reactome)
p-T235,S321-CEBPB:NF-kB:IL8 Gene:NucleosomeArrowR-HSA-3790137 (Reactome)
p-T235,S321-CEBPB:NF-kB:IL8 Gene:NucleosomeArrowR-HSA-3857308 (Reactome)
p-T235-CEBPBArrowR-HSA-3857329 (Reactome)
p-T235-CEBPBR-HSA-3857328 (Reactome)
ubiquitinR-HSA-3788724 (Reactome)

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