Cellular senescence induced by p53-ras cooperation is independent of p21waf1 in murine embryo fibroblasts.
Oncogenic activation in primary murine fibroblasts initiates a senescence-like cell cycle arrest that depends on the p53 tumor suppressor pathway. Conditional p53 activation efficiently induced a reversible cell cycle arrest but was unable to induce features of senescence. In contrast, coexpression of oncogenic ras with p53 produced an irreversible cell cycle arrest that displayed features of cellular senescence. Introduction of a conditional murine p53 allele (p53val135) into double p53/p21-null mouse embryonic fibroblasts showed that p21waf1 was not required for this effect, since p53-/-;p21-/- double-null cells undergo terminal growth arrest with features of senescence following coexpression of oncogenic Ras and p53. Our results indicate that oncogenic activation of the Ras pathway in murine fibroblasts converts p53 into a senescence inducer through a p21waf1-independent mechanism.
Castro
Maria E
ME
Experimental Therapeutics Program, Centro Nacional de Investigaciones Oncologicas (CNIO), Melchor Fernandez Almagro, 3, 28029, Madrid Spain.
del Valle Guijarro
Maria
M
Moneo
Victoria
V
Carnero
Amancio
A
D000818:Animals; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D016922:Cellular Senescence / Q000235:genetics / Q000502:physiology*; D050759:Cyclin-Dependent Kinase Inhibitor p21; D004622:Embryo, Mammalian / Q000166:cytology* / Q000378:metabolism; D005347:Fibroblasts / Q000166:cytology* / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D015689:Oncogene Protein p21(ras) / Q000235:genetics / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
C493957:Cdkn1a protein, mouse; D018797:Cell Cycle Proteins; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016159:Tumor Suppressor Protein p53; D015689:Oncogene Protein p21(ras)