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

Lin, A. W., Lowe, S. W. (April 2001) Oncogenic ras activates the ARF-p53 pathway to suppress epithelial cell transformation. Proceedings of the National Academy of Sciences of the United States of America, 98 (9). pp. 5025-5030. ISSN 0027-8424

URL: http://www.ncbi.nlm.nih.gov/pubmed/11309506
DOI: 10.1073/pnas.091100298

Abstract

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 acid was accompanied by increased expression of the p19(ARF), p16(INK4a), 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 p19(ARF), Mdm2 did not relocalize to the nucleolus or to nuclear bodies but remained distributed throughout the nucleoplasm, This result suggests that p19(ARF) 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.

Item Type: Paper
Uncontrolled Keywords: P19(ARF) TUMOR-SUPPRESSOR P53 GENE DOSAGE PREMATURE SENESCENCE MALIGNANT PROGRESSION EPIDERMAL-CELLS STABILIZES P53 INK4A LOCUS MDM2 MOUSE DIFFERENTIATION
Subjects: organs, tissues, organelles, cell types and functions > cell types and functions > cell types > epithelial cell
organs, tissues, organelles, cell types and functions > cell types and functions > cell types > epithelial cell
organs, tissues, organelles, cell types and functions > cell types and functions > cell types > epithelial cell

bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > genes, structure and function
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > genes, structure and function > genes: types > oncogene
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > genes, structure and function > genes: types > p53
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > G protein > Ras
CSHL Authors:
Communities: CSHL labs > Lowe lab
Depositing User: Matt Covey
Date: April 2001
Date Deposited: 17 Jan 2014 21:07
Last Modified: 17 Jan 2014 21:07
PMCID: PMC33157
Related URLs:
URI: http://repository.cshl.edu/id/eprint/29263

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