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 cycle arrest after a preset number of cell divisions. This process of 'replicative senescence' is activated in many cell types by the progressive erosion of the specialised ends of chromosomes--telomeres--which act as a molecular 'clock'. Although many details are still to be elucidated, one major signal pathway linking telomere shortening to growth arrest operates via activation of the tumour suppressor gene (TSG) product, p53, which in turn induces the cell-cycle inhibitor p21WAF1, and at least in some cell types wild-type p53 function is an absolute requirement for normal senescence. Given the evidence that replicative senescence represents a natural obstacle to tumour progression, the need to escape p53-mediated senescence may therefore represent a major selection pressure for loss of p53 function in many human cancers.