Senescence-Associated Secretory Phenotype (SASP)

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. In addition, oncogenic RAS signaling activates the CEBPB (C/EBP-beta) transcription factor, which binds promoters of IL6 and IL8 genes and stimulates their transcription. CEBPB also stimulates the transcription of CDKN2B (p15-INK4B), reinforcing the cell cycle arrest. 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, creating a positive feedback loop. NF-kappa-B transcription factor is also activated in senescence through IL1 signaling. NF-kappa-B binds IL6 and IL8 promoters and cooperates with CEBPB transcription factor in the induction of IL6 and IL8 transcription. Besides IL6 and IL8, their receptors are also upregulated in senescence 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.

Please refer to Young and Narita 2009 for a recent review.