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 journalArticle

65 Citations (Scopus)

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)1061-1066
Number of pages6
JournalEMBO Reports
Volume4
Issue number11
DOIs
StatePublished - Nov 1 2003

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Retinoblastoma
Cell Aging
Fibroblasts
Cyclin-Dependent Kinase 4
Small Interfering RNA
Tumors
Genes
Cells
Proteins
Loss of Heterozygosity
Homologous Recombination
Clone Cells
Phenotype
Neoplasms

All Science Journal Classification (ASJC) codes

  • Genetics
  • Molecular Biology
  • Biochemistry

Cite this

Wei, Wenyi ; Herbig, Utz ; Wei, Shan ; Dutriaux, Annie ; Sedivy, John M. / Loss of retinoblastoma but not p16 function allows bypass of replicative senescence in human fibroblasts. In: EMBO Reports. 2003 ; Vol. 4, No. 11. pp. 1061-1066.
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Loss of retinoblastoma but not p16 function allows bypass of replicative senescence in human fibroblasts. / Wei, Wenyi; Herbig, Utz; Wei, Shan; Dutriaux, Annie; Sedivy, John M.

In: EMBO Reports, Vol. 4, No. 11, 01.11.2003, p. 1061-1066.

Research output: Contribution to journalArticle

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