Regulation of the p21(Sdi1/Cip1/Waf1) DNA synthesis inhibitor in senescent human diploid fibroblasts

Ryan S. Robetorye, James R. Smith

Research output: Contribution to journalReview article

1 Scopus citations

Abstract

A large body of evidence has demonstrated that normal human fibroblasts have a limited division potential in culture and underwent senescence, a process whereby cells became arrested in the G1 phase of the cell cycle and overexpressed a DNA synthesis inhibitor(s). Cyclin-dependent kinase two (Cdk2) is required for the promotion of the G1-to-S phase transition in human cells. Senescent fibroblasts contain intact cyclin-Cdk2 complexes but cannot induce Cdk2 protein kinase activity in response to mitogen stimulation. Recently, we cloned p21(Sdi1), a potent inhibitor of DNA synthesis and Cdk2 kinase activity, from a senescent cell cDNA library and demonstrated that it was expressed at significantly higher levels in senescent cells than actively proliferating cells. In contrast to actively dividing cells, mitogen-stimulated senescent cells do not down-regulate the expression of p21(Sdi1) and do not express late G1 phase gene products that are required for entry into S phase. We suggest that the inability of mitogen-stimulated senescent cells to down-regulate p21(Sdi1) levels contributes to the resulting lack of late G1 gene expression and failure to traverse the G1/S phase boundary.

Original languageEnglish (US)
Pages (from-to)315-329
Number of pages15
JournalCanadian Journal on Aging
Volume15
Issue number2
DOIs
StatePublished - Jan 1 1996

Keywords

  • Cdk inhibitor
  • Cdk2
  • DNA synthesis
  • cell cycle
  • p21(Sdi1)

ASJC Scopus subject areas

  • Health(social science)
  • Gerontology
  • Community and Home Care
  • Geriatrics and Gerontology

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