Fig. 7. Pathways leading to reversible and essentially irreversible senescence growth arrests in human cells. Proliferating cells (Presenescent) arrest growth with a senescent phenotype in response to telomere erosion, which is p53 dependent, or a combination of telomere erosion and an as yet unidentified stimulus that induces p16. The p53-dependent arrest increases p21 expression, and is reversed by p53 inactivation or oncogenic Ras. p53 inactivation results in extensive proliferation (growth) culminating in crisis, whereas Ras causes limited proliferation. Cells that senesce with high p16 can be stimulated to synthesize DNA (S-phase) upon inactivation of p53 and pRb, or pRb inactivation plus oncogenic Ras, but do not proliferate (no growth).