TELOMERES, P53 AND CELLULAR SENESCENCE

The ability of mammalian cells to respond to extrinsic mitogens is dow nregulated in response to proliferative aging (senescence), and it is now likely that al least a subset of such lifespan checkpoints is trig gered by a biological ''clock'' based on erosion of chromosome telomer es. This review outlines the intrinsic inhibitory signal pathways that link this clock to cell cycle arrest, focussing on the role of tumour suppressor gene products, particularly the p53 and pRb proteins. Emph asis is placed on cell-type specific differences in the timing of life span checkpoints, and in the ''choice'' of the underlying inhibitory s ignal pathway. It is argued that such diversity may explain many diffe rences between cell types in the selection of tumour suppressor gene m utations, providing for example a novel explanation for the difference in molecular pathology and clinical behaviour between two important s ubsets of human breast cancer. Copyright (C) 1996 Elsevier Science Inc .