p19ARF‐independent induction of p53 and cell cycle arrest by Raf in murine keratinocytes

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Abstract
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 kinase pathway in primary mouse keratinocytes leads to a p53 and p21Cip1‐dependent cycle arrest and to terminal differentiation. Raf activation in keratinocytes lacking p53 or p21Cip1 genes leads to expression of differentiation markers, but the cells do not cease to proliferate. Thus, loss of p53 or p21 Cip1 function is necessary to disable growth‐inhibitory Raf/MAP kinase signalling. Activation of oncogenes, including Ras , has been reported to stabilize and activate p53 via induction of the tumour suppressor p19 ARF . However, the response to Raf in p19 ARF−/− keratinocytes was indistinguishable from wild‐type controls. Thus, p19 ARF is not essential for Raf‐induced p53 induction and cell cycle arrest in keratinocytes, indicating that oncogenes engage p53 activity via multiple mechanisms.