Figure 1. Senescence-inducing stimuli and main effector pathways.

A variety of cell-intrinsic and -extrinsic stresses can activate the cellular senescence program. These stressors engage various cellular signalling cascades but ultimately activate p53, p16^Ink4a, or both. Stress types that activate p53 through DDR signalling are indicated with grey text and arrows (ROS elicit the DDR by perturbing gene transcription and DNA replication, as well as by shortening telomeres). Activated p53 induces p21, which induces a temporal cell-cycle arrest by inhibiting cyclin E–Cdk2. p16^Ink4a also inhibits cell-cycle progression but does so by targeting cyclin D–Cdk4 and cyclin D–Cdk6 complexes. Both p21 and p16^Ink4a act by preventing the inactivation of Rb, thus resulting in continued repression of E2F target genes required for S-phase onset. Upon severe stress (red arrows), temporally arrested cells transition into a senescent growth arrest through a mechanism that is currently incompletely understood. Cells exposed to mild damage that can be successfully repaired may resume normal cell-cycle progression. On the other hand, cells exposed to moderate stress that is chronic in nature or that leaves permanent damage may resume proliferation through reliance on stress support pathways (green arrows). This phenomenon (termed assisted cycling) is enabled by p53-mediated activation of p21. Thus, the p53–p21 pathway can either antagonize or synergize with p16^Ink4a in senescence depending on the type and level of stress. BRAF(V600E) is unusual in that it establishes senescence through a metabolic effector pathway. BRAF(V600E) activates PDH by inducing PDP2 and inhibiting PDK1 expression, promoting a shift from glycolysis to oxidative phosphorylation that creates senescence-inducing redox stress. Cells undergoing senescence induce an inflammatory transcriptome regardless of the senescence inducing stress (coloured dots represent various SASP factors). Red and green connectors indicate ‘senescence-promoting’ and ‘senescence-preventing’ activities, respectively, and their thickness represents their relative importance. The dashed green connector denotes a ‘senescence-reversing’ mechanism.