Loss of retinoblastoma but not p16 function allows bypass of replicative senescence in human fibroblasts

Wenyi Wei, Utz Herbig, Shan Wei, Annie Dutriaux, John M. Sedivy

Research output: Contribution to journalArticlepeer-review

69 Scopus citations

Abstract

Current models envision replicative senescence to be under dual control by the p53 and retinoblastoma (RB) tumour-suppressor pathways. The role of the p16INK4a-RB pathway is controversial, and the function of RB in human cells has not been tested directly. We used targeted homologous recombination to knock out one copy of RB in presenescent human fibroblasts. During entry into senescence, RB+/- cells underwent spontaneous loss of heterozygosity and the resultant RB-/- clones bypassed senescence. The extended lifespan phase was eventually terminated by a crisis-like state. The same phenotype was documented for p21CIP1/WAF1 and p53 heterozygous cells, indicating that loss of function of all three genes results in failure to establish senescence. By contrast, the abolition of p16 function by the expression of a p16-insensitive cyclin-dependent kinase 4 protein or siRNA-mediated knockdown provided only minimal lifespan extension that was terminated by senescence. We propose that p53, p21 and RR act in a linear genetic pathway to regulate cell entry into replicative senescence.

Original languageEnglish (US)
Pages (from-to)1061-1065
Number of pages5
JournalEMBO Reports
Volume4
Issue number11
DOIs
StatePublished - Nov 2003
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Genetics

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