Evidence that transcriptional activation by p53 plays a direct role in the induction of cellular senescence.

摘要: Wild-type p53 is necessary for the growth arrest of human diploid fibroblasts (HDF) (and many other cell types) at end their proliferative lifespan. Although may actively mediate senescence, possibly in response to telomere erosion, it however equally possible that merely a permissive factor required some inducer. To address this question, we have generated stable transfectants early passage HDF, represented here by clone LacZ21, which expression beta-galactosidase reporter construct reflects transactivation activity. During continuous passage, proportion beta-gal positive LacZ21 cells remained below 2% 25 population doublings (pd), first became significantly increased after 29 pd, and thereafter rapidly, reaching maximum 88% fully-senescent (32 pd), exceeded observed following an optimum dose (20 J/m2) u.v. radiation. Correspondingly, incorporating bromodeoxyuridine (BrdU) (initially 45-50%) began fall pd dropped rapidly 1% 32. There was therefore near-perfect reciprocal relationship between DNA synthesis as approached senescence. Furthermore, dominant-negative mutant (introduced retroviral transduction) rescued from senescence colonies with extended lifespan totally abolished. These data, although not excluding need functions, strongly suggest p53-mediated regulatory genes direct trigger, rather than factor, cellular