Dual Inactivation of RB and p53 Pathways in RAS-Induced Melanomas

doi:10.1128/MCB.21.6.2144-2153.2001

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Molecular and Cellular Biology, March 2001, p. 2144-2153, Vol. 21, No. 6
0270-7306/01/$04.00+0 DOI: 10.1128/MCB.21.6.2144-2153.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Dual Inactivation of RB and p53 Pathways in RAS-Induced Melanomas

Nabeel Bardeesy,¹ Boris C. Bastian,²^,³ Aram Hezel,¹ Dan Pinkel,³ Ronald A. DePinho,¹^,⁴ and Lynda Chin¹^,⁵^,^*

Department of Adult Oncology, Dana-Farber Cancer Institute,¹ Department of Medicine and Genetics,⁴ and Department of Dermatology,⁵ Harvard Medical School, Boston, Massachusetts, and Departments of Dermatology and Pathology,² and Comprehensive Cancer Center,³ University of California, San Francisco, California

Received 26 June 2000/Accepted 14 November 2000

The frequent loss of both INK4a and ARF in melanoma raises the question of which INK4a-ARF gene product functions to suppressmelanoma genesis in vivo. Moreover, the high incidence of INK4a-ARFinactivation in transformed melanocytes, along with the lack ofp53 mutation, implies a cell type-specific role for INK4a-ARFthat may not be complemented by other lesions of the RB and p53pathways. A mouse model of cutaneous melanoma has been generatedpreviously through the combined effects of INK4a^2/3 deficiency (null for INK4a and ARF) and melanocyte-specific expressionof activated RAS (tyrosinase-driven H-RAS^V12G, Tyr-RAS). In this study, we made use of this Tyr-RAS alleleto determine whether activated RAS can cooperate with p53 lossin melanoma genesis, whether such melanomas are biologically comparableto those arising in INK4a^2/3/ mice, and whether tumor-associated mutations emerge in the p16^INK4a-RB pathway in such melanomas. Here, we report that p53 inactivationcan cooperate with activated RAS to promote the development ofcutaneous melanomas that are clinically indistinguishable fromthose arisen on the INK4a^2/3 null background. Genomewide analysis of RAS-induced p53 mutantmelanomas by comparative genomic hybridization and candidate genesurveys revealed alterations of key components governing RB-regulatedG₁/S transition, including c-Myc, cyclin D1, cdc25a, and p21^CIP1. Consistent with the profile of c-Myc dysregulation, the reintroductionof p16^INK4a profoundly reduced the growth of Tyr-RAS INK4a^2/3/ tumor cells but had no effect on tumor cells derived from Tyr-RASp53^/ melanomas. Together, these data validate a role for p53 inactivationin melanomagenesis and suggest that both the RB and p53 pathwaysfunction to suppress melanocyte transformation in vivo in themouse.

^* Corresponding author. Mailing address: Department of Adult Oncology, Dana-Farber Cancer Institute, 44 Binney St., Boston,MA 02115. Phone: (617) 632-6091. Fax: (617) 632-6069. E-mail:lynda_chin{at}dfci.harvard.edu.

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