Senescence-associated secretory phenotype (SASP) (WP3391)

Homo sapiens

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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.

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).

Please refer to Young and Narita 2009 for a recent review. View original pathway at [http://www.reactome.org/PathwayBrowser/#DIAGRAM=2559582 Reactome].

Authors

ReactomeTeam , Vinny Lynch , and Eric Weitz

Activity

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Organisms

Homo sapiens

Communities

Annotations

Participants
Query Drugst.One

Label Type Compact URI Comment
ATP Metabolite chebi:30616
ADP Metabolite chebi:456216
AdoMet Metabolite chebi:15414
AdoHcy Metabolite chebi:16680
IL6 gene GeneProduct ensembl:ENSG00000136244
CEBPB gene GeneProduct ensembl:ENSG00000172216
IL1A gene GeneProduct ensembl:ENSG00000115008
IL8 gene GeneProduct ensembl:ENSG00000169429
CDKN2B gene GeneProduct ensembl:ENSG00000147883
IGFBP7 gene GeneProduct ensembl:ENSG00000163453
ANAPC15 Protein uniprot:P60006
IL6 gene Protein ensembl:ENSG00000136244
RPS27A(1-76) Protein uniprot:P62979
ANAPC16 Protein uniprot:Q96DE5
IL8 gene Protein ensembl:ENSG00000169429
UBE2S Protein uniprot:Q16763
p-T235, S321-CEBPB Protein uniprot:P17676
HIST1H2AB Protein uniprot:P04908
UBC(381-456) Protein uniprot:P0CG48
HIST2H2BE Protein uniprot:Q16778
UBE2C Protein uniprot:O00762
CCNA1 Protein uniprot:P78396
H2AFJ Protein uniprot:Q9BTM1
HIST1H2BD Protein uniprot:P58876
UBE2E1 Protein uniprot:P51965
HIST1H2BK Protein uniprot:O60814
H2AFV Protein uniprot:Q71UI9
ANAPC10 Protein uniprot:Q9UM13
UBC(305-380) Protein uniprot:P0CG48
HIST1H2AC Protein uniprot:Q93077
HIST1H2BB Protein uniprot:P33778
UBE2D1 Protein uniprot:P51668
ANAPC4 Protein uniprot:Q9UJX5
ANAPC1 Protein uniprot:Q9H1A4
p-T235, S321-CEBPB Protein uniprot:P17676
H3F3A Protein uniprot:P84243
CDC16 Protein uniprot:Q13042
p-S63,S73-JUN Protein uniprot:P05412
ANAPC11 Protein uniprot:Q9NYG5
CDC23 Protein uniprot:Q9UJX2
H2BFS Protein uniprot:P57053
p-T202,Y204-MAPK3 Protein uniprot:P27361
CCNA2 Protein uniprot:P20248
UBA52(1-76) Protein uniprot:P62987
HIST1H2AD Protein uniprot:P20671
CDKN2C Protein uniprot:P42773
HIST1H2BL Protein uniprot:Q99880
HIST1H2BA Protein uniprot:Q96A08
RPS6KA3 Protein uniprot:P51812
Me2K-10-HIST2H3A Protein uniprot:Q71DI3
p-T325,T331,S362,S374-FOS Protein uniprot:P01100
Myr82K-Myr83K-IL1A Protein uniprot:P01583
ANAPC5 Protein uniprot:Q9UJX4
CDC26 Protein uniprot:Q8NHZ8
CDKN2B Protein uniprot:P42772
HIST2H2AC Protein uniprot:Q16777
HIST1H2BM Protein uniprot:Q99879
RPS6KA2 Protein uniprot:Q15349
H2AFX Protein uniprot:P16104
ANAPC2 Protein uniprot:Q9UJX6
CEBPB Protein uniprot:P17676
IL8 Protein uniprot:P10145
UBB(77-152) Protein uniprot:P0CG47
UBC(609-684) Protein uniprot:P0CG48
HIST2H3A Protein uniprot:Q71DI3
HIST2H2AA3 Protein uniprot:Q6FI13
H2AFZ Protein uniprot:P0C0S5
HIST1H2AJ Protein uniprot:Q99878
UBC(77-152) Protein uniprot:P0CG48
CDC27 Protein uniprot:P30260
p-T185,Y187-MAPK1 Protein uniprot:P28482
CDKN1B Protein uniprot:P46527
CDK6 Protein uniprot:Q00534
IL1A gene Protein ensembl:ENSG00000115008
EHMT2 Protein uniprot:Q96KQ7
HIST1H3A Protein uniprot:P68431
ANAPC7 Protein uniprot:Q9UJX3
HIST1H2BC Protein uniprot:P62807
RELA Protein uniprot:Q04206
HIST1H2BJ Protein uniprot:P06899
UBC(1-76) Protein uniprot:P0CG48
p16INK4A Protein uniprot:P42771
CDKN2B Protein uniprot:P42772
FZR1 Protein uniprot:Q9UM11
CDKN2D Protein uniprot:P55273
HIST1H2BO Protein uniprot:P23527
HIST1H2BH Protein uniprot:Q93079
UBB(1-76) Protein uniprot:P0CG47
HIST1H2BN Protein uniprot:Q99877
H2AFB1 Protein uniprot:P0C5Y9
Me2K10-HIST1H3A Protein uniprot:P68431
CDK4 Protein uniprot:P11802
HIST1H4 Protein uniprot:P62805
UBC(153-228) Protein uniprot:P0CG48
EHMT1 Protein uniprot:Q9H9B1
VENTX Protein uniprot:O95231
UBB(153-228) Protein uniprot:P0CG47
UBC(229-304) Protein uniprot:P0CG48
p-T160-CDK2 Protein uniprot:P24941
p-4S,T356,T570-RPS6KA2 Protein uniprot:Q15349
UBC(533-608) Protein uniprot:P0CG48
HIST3H2BB Protein uniprot:Q8N257
IL6 Protein uniprot:P05231
p-4S,T231,T365-RPS6KA3 Protein uniprot:P51812
NFKB1(1-433) Protein uniprot:P19838
CDKN1A Protein uniprot:P38936
Me2K-10-H3F3A Protein uniprot:P84243
IGFBP7 gene Protein ensembl:ENSG00000163453
p-Y705-STAT3 Protein uniprot:P40763
UBC(457-532) Protein uniprot:P0CG48
p-FZR1 Protein uniprot:Q9UM11
p-T235-CEBPB Protein uniprot:P17676
IGFBP7 Protein uniprot:Q16270
RPS6KA1 Protein uniprot:Q15418
p-4S,T359,T573-RPS6KA1 Protein uniprot:Q15418
CDKN2B gene Protein ensembl:ENSG00000147883
CDK2 Protein uniprot:P24941
p-T218,Y220-MAPK7 Protein uniprot:Q13164

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