In tumorigenesis of the skin, activated Ras co-operates with mutations that
inactivate the tumour suppressor p53, but the molecular basis for this co-
operation remains unresolved. Here we show that activation of the Raf/MAP k
inase pathway in primary mouse keratinocytes leads to a p53 and p21(Cip1)-d
ependent cycle arrest and to terminal differentiation. Raf activation in ke
ratinocytes lacking p53 or p21(Cip1) genes leads to expression of different
iation markers, but the cells do not cease to proliferate. Thus, loss of p5
3 or p21(Cip1) function is necessary to disable growth-inhibitory Raf/MAP k
inase signalling. Activation of oncogenes, including Ras, has been reported
to stabilize and activate p53 via induction of the tumour suppressor p19(A
RF). However, the response to Raf in p19(ARF-/-) keratinocytes was indistin
guishable from wild-type controls. Thus, p19(ARF) is not essential for Raf-
induced p53 induction and cell cycle arrest in keratinocytes, indicating th
at oncogenes engage p53 activity via multiple mechanisms.