Figure 3. The SASP is regulated at multiple levels.

When faced with senescence-inducing cellular stressors such as UVR, oncogene activation, and aging, the ATM-mediated DDR is activated during the S-phase checkpoint (for which MLL1 is required). The DDR in turn activates a number of downstream transcription factors and kinases, including NF-κB, p38MAPK, PKD1, CEBPβ, and GATA4. In conjunction with epigenetic remodeling (coordinated through chromatin regulators Sirt1 and Brd4), as well as translational regulation via mTOR, this results in massive upregulation of SASP cytokines, proteases, and growth factors. ATM, ataxia telangiectasia mutated; DDR, DNA-damage response; MAPK, mitogen-activated protein kinase; MLL1, mixed-lineage leukemia 1; MMP1, matrix metalloproteinase 1; mTOR, mammalian target of rapamycin; PKD1, protein kinase D1; SASP, senescence-associated secretory phenotype.