Proliferative lifespan checkpoints: cell-type specificity and influence on tumour biology

Lifespan checkpoints are viewed here as intrinsic mechanisms which desensitise cells to external growth signals as a programmed response to proliferative age, as distinct from externally-triggered differentiation. This review focuses on the role of tumour suppressor gene products as essential mediators of cell cycle arrest at lifespan checkpoints, concentrating in particular on p53. Although drawing inevitably on fibroblast senescence and telomere erosion paradigms, other lifespan clocks and signal pathways are discussed. Particular emphasis is placed on cell-type diversity in the nature, number and timing of lifespan checkpoints and its importance for tumour biology. Breast and thyroid cancer are used to illustrate the concept that the "choice" of checkpoint(s) in a given normal cell may have a determining influence on the mutational spectrum and clinical behaviour of its tumours.