Cellular and molecular mechanisms of stress-induced premature senescence (SIPS) of human diploid fibroblasts and melanocytes

Replicative senescence of human diploid fibroblasts (HDFs) or melanocytes i s caused by the exhaustion of their proliferative potential. Stress-induced premature senescence (SIPS) occurs after many different sublethal stresses including H2O2, hyperoxia, or tert-butylhydroperoxide. Cells in replicativ e senescence share common features with cells in SIPS: morphology, senescen ce-associated beta -galactosidase activity, cell cycle regulation, gene exp ression and telomere shortening. Telamere shortening is attributed to the a ccumulation of DNA single-strand breaks induced by oxidative damage. SIPS c ould be a mechanism of accumulation of senescent-like cells in vivo. Melano cytes exposed to sublethal doses of UVB undergo SIPS. Melanocytes from dark - and light- skinned populations display differences in their cell cycle re gulation. Delayed SIPS occurs in melanocytes from light-skinned populations since a reduced association of p16(Ink-4a) with CDK4 and reduced phosphory lation of the retinoblastoma protein are observed. The role of reactive oxy gen species in melanocyte SIPS is unclear. Both replicative senescence and SIPS are dependent on two major pathways. One is triggered by DNA damage, t elomere damage and/or shortening and involves the activation of the p53 and p21(waf-1) proteins. The second pathway results in the accumulation of p16 (Ink-4a) with the MAP kinase signalling pathway as possible intermediate. T hese data corroborate the thermodynamical theory of ageing, according to wh ich the exposure of cells to sublethal stresses of various natures can trig ger SIPS, with possible modulations of this process by bioenergetics. (C) 2 000 Elsevier Science Inc. All rights reserved.