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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 suppress melanoma genesis in vivo. Moreover, the high incidence of INK4a-ARF inactivation in transformed melanocytes, along with the lack of p53 mutation, implies a cell type-specific role for INK4a-ARF that may not be complemented by other lesions of the RB and p53 pathways. A mouse model of cutaneous melanoma has been generated previously through the combined effects of INK4aDelta 2/3 deficiency (null for INK4a and ARF) and melanocyte-specific expression of activated RAS (tyrosinase-driven H-RASV12G, Tyr-RAS). In this study, we made use of this Tyr-RAS allele to determine whether activated RAS can cooperate with p53 loss in melanoma genesis, whether such melanomas are biologically comparable to those arising in INK4aDelta 2/3-/- mice, and whether tumor-associated mutations emerge in the p16INK4a-RB pathway in such melanomas. Here, we report that p53 inactivation can cooperate with activated RAS to promote the development of cutaneous melanomas that are clinically indistinguishable from those arisen on the INK4aDelta 2/3 null background. Genomewide analysis of RAS-induced p53 mutant melanomas by comparative genomic hybridization and candidate gene surveys revealed alterations of key components governing RB-regulated G1/S transition, including c-Myc, cyclin D1, cdc25a, and p21CIP1. Consistent with the profile of c-Myc dysregulation, the reintroduction of p16INK4a profoundly reduced the growth of Tyr-RAS INK4aDelta 2/3-/- tumor cells but had no effect on tumor cells derived from Tyr-RAS p53-/- melanomas. Together, these data validate a role for p53 inactivation in melanomagenesis and suggest that both the RB and p53 pathways function to suppress melanocyte transformation in vivo in the mouse.

* 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.

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.


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