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PMID: 11238948 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S.

Dual inactivation of RB and p53 pathways in RAS-induced melanomas.

Molecular and cellular biology ·Vol. 21 ·No. 6 ·2001-03-00 ·Pages 2144-53

Bardeesy N, Bastian BC, Hezel A, Pinkel D, DePinho RA, Chin L

Abstract

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 INK4a(Delta2/3) deficiency (null for INK4a and ARF) and melanocyte-specific expression of activated RAS (tyrosinase-driven H-RAS(V12G), 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 INK4a(Delta2/3-/-) mice, and whether tumor-associated mutations emerge in the p16(INK4a)-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 INK4a(Delta2/3) 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 G(1)/S transition, including c-Myc, cyclin D1, cdc25a, and p21(CIP1). Consistent with the profile of c-Myc dysregulation, the reintroduction of p16(INK4a) profoundly reduced the growth of Tyr-RAS INK4a(Delta2/3-/-) 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.

MeSH Terms
Animals Cyclin D1/genetics,metabolism Cyclin-Dependent Kinase Inhibitor p16/genetics,metabolism Cyclin-Dependent Kinase Inhibitor p21 Cyclins/genetics,metabolism G1 Phase/genetics Gene Expression Regulation, Neoplastic Gene Silencing Genes, ras In Situ Hybridization/methods Melanoma/genetics,metabolism Mice Mice, Mutant Strains Proteins/genetics,metabolism Proto-Oncogene Proteins c-myc/genetics,metabolism Retinoblastoma Protein/genetics,metabolism S Phase/genetics Tumor Suppressor Protein p14ARF Tumor Suppressor Protein p53/genetics,metabolism cdc25 Phosphatases/genetics,metabolism
Chemicals
Cdkn1a protein, mouse Cyclin-Dependent Kinase Inhibitor p16 Cyclin-Dependent Kinase Inhibitor p21 Cyclins Myc protein, mouse Proteins Proto-Oncogene Proteins c-myc Retinoblastoma Protein Tumor Suppressor Protein p14ARF Tumor Suppressor Protein p53 Cyclin D1 Cdc25a protein, mouse cdc25 Phosphatases
Authors & Affiliations
6 authors, click to expand affiliations / ORCID
Bardeesy N
Department of Adult Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115, USA.
Bastian B C
Hezel A
Pinkel D
DePinho R A
Chin L
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Article Info
Journal
Molecular and cellular biology
Abbr.
Mol Cell Biol
ISSN
0270-7306
DOI
10.1128/MCB.21.6.2144-2153.2001
Published
2001-03-00
Pages
2144-53
Language
English
Region
United States
NLM ID
8109087
PMCID
PMC86838
Subset
IM
Grants
NCI NIH HHS · U01 CA084313 · United States
NIAMS NIH HHS · K08AR02104-01 · United States
NCI NIH HHS · U01CA84313-01 · United States
External Links
PubMed source DOI: 10.1128/MCB.21.6.2144-2153.2001 PMC Full Text View journal details
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