Ha, L., Ichikawa, T., Anver, M., Dickins, R. A., Lowe, S. W., Sharpless, N E., Krimpenfort, P , DePinho, R. A., Bennett, D. C., Sviderskaya, E. V., Merlino, G. (June 2007) ARF functions as a melanoma tumor suppressor by inducing p53-independent senescence. Proc Natl Acad Sci U S A, 104 (26). 10968-10973 . ISSN 0027-8424 (Print)
Preview |
PDF (Paper)
Lowe PNAS 2007.pdf - Published Version Download (2MB) | Preview |
Abstract
Inactivation of the p53 pathway represents the most common molecular defect of human cancer. But in the setting of melanoma, a highly aggressive and invariably fatal malignancy in its advanced disseminated form, mutation/deletion of p53 is relatively rare, whereas its positive regulator ARF is often lost. Here, we show that genetic deficiency in Arf but not p53 facilitates rapid development of melanoma in a genetically engineered mouse model. This difference is accounted for, at least in part, by the unanticipated observation that, unlike fibroblasts, senescence control in melanocytes is strongly regulated by Arf and not p53. Moreover, oncogenic NRAS collaborates with deficiency in Arf, but not p53, to fully transform melanocytes. Our data demonstrate that ARF and p53, although linked in a common pathway, suppress tumorigenesis through distinct, lineage-dependent mechanisms and suggest that ARF helps restrict melanoma progression by executing the oncogene-induced senescence program in benign nevi. Thus, therapeutics designed to restore wild-type p53 function may be insufficient to counter melanoma and other malignancies in which ARF holds p53-independent tumor suppressor activity.
| Item Type: | Paper |
|---|---|
| Uncontrolled Keywords: | genetically engineered mice MET nevi p16INK4A rhabdomyosarcoma |
| Subjects: | bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > genes, structure and function > genes: types > ARF diseases & disorders > cancer diseases & disorders > cancer > cancer types > melanomas bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > genes, structure and function > genes: types > p53 |
| CSHL Authors: | |
| Communities: | CSHL labs > Lowe lab |
| Depositing User: | CSHL Librarian |
| Date: | 26 June 2007 |
| Date Deposited: | 15 Nov 2011 14:41 |
| Last Modified: | 09 Nov 2017 15:52 |
| PMCID: | PMC1904138 |
| Related URLs: | |
| URI: | https://repository.cshl.edu/id/eprint/23024 |
Actions (login required)
 |
Administrator's edit/view item |