p19ARF-independent induction of p53 and cell cycle arrest by Raf in murine keratinocytes.
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 p21Cip1 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 p19ARF. However, the response to Raf in p19ARFI-/- keratinocytes was indistinguishable from wild-type controls. Thus, p19ARF is not essential for Raf-induced p53 induction and cell cycle arrest in keratinocytes, indicating that oncogenes engage p53 activity via multiple mechanisms.
Imperial Cancer Research Fund, London, UK.
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E
Roper
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W
Weinberg
F M
FM
Watt
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Land
D000818:Animals; D015153:Blotting, Western; D002453:Cell Cycle; D002454:Cell Differentiation; D002455:Cell Division; D048429:Cell Size; D002478:Cells, Cultured; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000235:genetics / Q000378:metabolism; D004789:Enzyme Activation; D017353:Gene Deletion; D015603:Keratinocytes / Q000166:cytology* / Q000201:enzymology / Q000378:metabolism*; D020935:MAP Kinase Signaling System; D051379:Mice; D011498:Protein Precursors / Q000032:analysis; D011506:Proteins / Q000235:genetics / Q000502:physiology*; D019908:Proto-Oncogene Proteins c-raf / Q000378:metabolism*; D014161:Transduction, Genetic; D025803:Tumor Suppressor Protein p14ARF; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*; D018631:ras Proteins / Q000378:metabolism
C493957:Cdkn1a protein, mouse; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D011498:Protein Precursors; D011506:Proteins; D025803:Tumor Suppressor Protein p14ARF; D016159:Tumor Suppressor Protein p53; C032253:involucrin; D019908:Proto-Oncogene Proteins c-raf; D018631:ras Proteins