Oncogenic activation of the mitogen-activated protein (MAP) kinase cascade in 
murine fibroblasts initiates a senescence-like cell cycle arrest that depends on 
the ARF/p53 tumor suppressor pathway. To investigate whether p53 is sufficient 
to induce senescence, we introduced a conditional murine p53 allele 
(p53(val135)) into p53-null mouse embryonic fibroblasts and examined cell 
proliferation and senescence in cells expressing p53, oncogenic Ras, or both 
gene products. Conditional p53 activation efficiently induced a reversible cell 
cycle arrest but was unable to induce features of senescence. In contrast, 
coexpression of oncogenic ras or activated mek1 with p53 enhanced both p53 
levels and activity relative to that observed for p53 alone and produced an 
irreversible cell cycle arrest that displayed features of cellular senescence. 
p19(ARF) was required for this effect, since p53(-/-) ARF(-/-) double-null cells 
were unable to undergo senescence following coexpression of oncogenic Ras and 
p53. Although the levels of exogenous p53 achieved in ARF-null cells were 
relatively low, the stabilizing effects of p19(ARF) on p53 could not explain the 
cooperation between oncogenic Ras and p53 in promoting senescence. Hence, 
enforced p53 expression without oncogenic ras in p53(-/-) mdm2(-/-) double-null 
cells produced extremely high p53 levels but did not induce senescence. Taken 
together, our results indicate that oncogenic activation of the MAP kinase 
pathway in murine fibroblasts converts p53 into a senescence inducer through 
both quantitative and qualitative mechanisms.