Origins of G1 arrest in senescent human fibroblasts

Bioessays. 1995 Jun;17(6):537-43. doi: 10.1002/bies.950170610.

Abstract

Human diploid fibroblasts have a finite proliferative lifespan in culture, at the end of which they are arrested with G1 phase DNA contents. Upon serum stimulation, senescent cells are deficient in carrying out a subset of early signal transduction events such as activation of protein kinase C and induction of c-fos. Later in G1, they uniformly fail to express late G1 genes whose products are required for DNA synthesis, implying that they are unable to pass the R point. Failure to pass the R point may occur because senescent cells are unable to phosphorylate the retinoblastoma protein, owing to the accumulation of inactive complexes of cyclin E/Cdk2 and possibly cyclin D/Cdk4. Senescent cells contain high amounts of p21, a potent cyclin-dependent kinase inhibitor whose levels are also elevated in cells arrested in G1 following DNA damage, suggesting that both arrests might share a common mechanism. Cell aging is accompanied by a progressive shortening of chromosomal telomeres, which could be perceived by the cells as a form of DNA damage that gives rise to the signals that inactive the cell cycle machinery.

Publication types

  • Research Support, U.S. Gov't, P.H.S.
  • Review

MeSH terms

  • Cell Cycle*
  • Cellular Senescence*
  • Cyclin-Dependent Kinases / metabolism*
  • Cyclins / metabolism*
  • DNA / biosynthesis
  • DNA / metabolism
  • DNA Damage
  • Fibroblasts / cytology
  • Fibroblasts / physiology
  • G1 Phase*
  • Humans
  • Models, Biological

Substances

  • Cyclins
  • DNA
  • Cyclin-Dependent Kinases