Replicative senescence as a barrier to human cancer

There is evidence that one critically short telomere may be recognized as D NA damage and, as a consequence, induce a p53/p21(WAF)- and p16(INK4A)- dep endent G1 cell cycle checkpoint to cause senescence. Additionally, senescen ce via a p53- and p16(INK4A)-dependent mechanism can be Induced by the over - or under-stimulation of certain signalling pathways that are involved in cancer. Central to this alternative senescence mechanism is the p14(ARF) pr otein, which connects oncogene activation, but not DNA damage, to p53 activ ation and senescence. We find that immortal keratinocytes almost invariably have dysfunctional p53 and p16 and have high levels of telomerase, but ver y often express a wild-type p14(ARF). Furthermore, when normal keratinocyte s senesce they show a striking elevation of p16 protein, but not of p14(ARF ) Or its downstream targets p53 and p21(WAF). These results suggest that p1 6, rather than p14(ARF), is the more important gene in human keratinocyte s enescence, but do not exclude a co-operative role for p14(ARF), perhaps in the induction of senescence by activated oncogenes in neoplasia. Regardless of mechanism, these results suggest that replicative senescence acts as a barrier to human cancer development.