Growth Arrest

One of the defining characteristics of senescent cells is their stable and essentially irreversible arrest of cell proliferation. Senescent cells arrest growth with a G1 DNA content. Once this growth arrest occurs, physiological mitogens cannot stimulate senescent cells to enter the S phase of the cell cycle (27,28,91,92). This failure to initiate DNA replication in response to mitogens is not caused by a general breakdown in growth factor signal transduction, although selected signal transduction components are altered in senescent cells (93-96). Rather the immediate cause of the growth arrest appears to be the repression of a subset of growth-stimulatory genes and the upregulation of a subset of growth-inhibitory genes. The senescence-associated changes in growth regulatory gene expression have been most clearly established for cultured human fibroblasts, in which replicative senescence and the mitogen responsiveness of many genes have been extensively characterized.

In senescent human fibroblasts, many genes, including at least three pro-tooncogenes (JUN, MYC, and RAS-Ha), remain mitogen inducible (97-99). However, at least three mitogen-inducible, growth-stimulatory genes become repressed in senescent fibroblasts (FOS, E2F1, and ID) (99-101). Repression of these genes very likely causes or contributes to the senescence growth arrest, because restoration of FOS, E2F1, and ID expression in varying combinations can at least partially restore the ability of senescent cells to initiate DNA synthesis (102-104).

In addition to the repression of growth-stimulatory genes, senescent cells overexpress at least two potent growth-inhibitory proteins. These proteins are the p16 and p21 CDKIs (inhibitors of cyclin-dependent protein kinases) (105-110). Both p16 and p21 are important regulators of the pRB and p53 tumor suppressor pathways, respectively, and both are critical for establishing and maintaining the senescence growth arrest (11,84,85,111). Moreover, ectopic overexpression of p16 or p21 causes human fibroblasts to arrest growth with a senescent pheno-type (112,113). These findings suggest that overexpression of p21 and p16 may act upstream of the repression of FOS, E2F, and other genes, and can at least partly, if not completely, explain the senescence-associated growth arrest (84,85,114).

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