ORIGINS OF G(1) ARREST IN SENESCENT HUMAN FIBROBLASTS

Human diploid fibroblasts have a finite proliferative lifespan in cult ure, at the end of which they are arrested with G(1) phase DNA content s. Upon serum stimulation, senescent cells are deficient in carrying o ut a subset of early signal transduction events such as activation of protein kinase C and induction of c-fos. Later in G(1), they uniformly fail to express late G(1) genes whose products are required for DNA s ynthesis, implying that they are unable to pass the R point. Failure t o pass the R point may occur because senescent cells are unable to pho sphorylate the retinoblastoma protein, owing to the accumulation of in active complexes of cyclin E/Cdk2 and possibly cyclin D/Cdk4. Senescen t cells contain high amounts of p21, a potent cyclin-dependent kinase inhibitor whose levels are also elevated in cells arrested in G(1) fol lowing DNA damage, suggesting that both arrests might share a common m echanism. Cell aging is accompanied by a progressive shortening of chr omosomal telomeres, which could be perceived by the cells as a form of DNA damage that gives rise to the signals that inactivate the cell cy cle machinery.