Replicative senescence: mechanisms and implications for human cancer

The proliferative lifespan of most normal human cells, even in ideal growth conditions, is limited by intrinsic inhibitory signals which induce cell c ycle arrest after a preset number of cell divisions. This process of 'repli cative senescence' is activated in many cell types by the progressive erosi on of the specialised ends of chromosomes - telomeres - which act as a mole cular 'clock'. Although many details are still to be elucidated, one major signal pathway linking telomere shortening to growth arrest operates via ac tivation of the tumour suppressor gene (TSG) product, p53, which in turn in duces the cell-cycle inhibitor p21(WAF1), and at least in some cell types w ild-type p53 function is an absolute requirement for normal senescence. Giv en the evidence that replicative senescence represents a natural obstacle t o tumour progression, the need to escape p53-mediated senescence may theref ore represent a major selection pressure for loss of p53 function in many h uman cancers. (C) 2000 Editions scientifiques et medicales Elsevier SAS.