Oncogenic ras activates the ARF-p53 pathway to suppress epithelial cell transformation

AW Lin, SW Lowe - … of the National Academy of Sciences, 2001 - National Acad Sciences
AW Lin, SW Lowe
Proceedings of the National Academy of Sciences, 2001National Acad Sciences
Chemically induced skin carcinomas in mice are a paradigm for epithelial neoplasia, where
oncogenic ras mutations precede p53 and INK4a/ARF mutations during the progression
toward malignancy. To explore the biological basis for these genetic interactions, we studied
cellular responses to oncogenic ras in primary murine keratinocytes. In wild-type
keratinocytes, ras induced a cell-cycle arrest that displayed some features of terminal
differentiation and was accompanied by increased expression of the p19ARF, p16INK4a …
Chemically induced skin carcinomas in mice are a paradigm for epithelial neoplasia, where oncogenic ras mutations precede p53 and INK4a/ARF mutations during the progression toward malignancy. To explore the biological basis for these genetic interactions, we studied cellular responses to oncogenic ras in primary murine keratinocytes. In wild-type keratinocytes, ras induced a cell-cycle arrest that displayed some features of terminal differentiation and was accompanied by increased expression of the p19ARF, p16INK4a, and p53 tumor suppressors. In ARF-null keratinocytes, ras was unable to promote cell-cycle arrest, induce differentiation markers, or properly activate p53. Although oncogenic ras produced a substantial increase in both nucleolar and nucleoplasmic p19ARF, Mdm2 did not relocalize to the nucleolus or to nuclear bodies but remained distributed throughout the nucleoplasm. This result suggests that p19ARF can activate p53 without overtly affecting Mdm2 subcellular localization. Nevertheless, like p53-null keratinocytes, ARF-null keratinocytes were transformed by oncogenic ras and rapidly formed carcinomas in vivo. Thus, oncogenic ras can activate the ARF-p53 program to suppress epithelial cell transformation. Disruption of this program may be important during skin carcinogenesis and the development of other carcinomas.
National Acad Sciences