Reference SummaryBardeesy N, Mol Cell Biol 2001 Mar;21(6):2144-53

Title

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

Authors

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

Journal

 Mol Cell Biol

Volume

 21

Issue

 6

Year

 2001

Pages

 2144-53

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.

Links

 J:67799 – MGI References
11238948 – National Library of Medicine/PubMed

Strain Notes

Strain Note
[not specified]-Cdkn2atm1Rdp Tg(Tyr-HRAS)60Lc Animals were of mixed background (65% C57BL/6, 25% CBA, 10% "129/Sv") or N3 generation FVB backcross (83% FVB)(sic).
[not specified]-Tg(Tyr-HRAS)60Lc Trp53tm1Tyj Animals were of mixed background (80% C57BL/6, 20% "129/Sv") or N1 generation FVB backcross (50% FVB, 40% C57BL/6)(sic).
[not specified]-Tg(Tyr-HRAS)60Lc Trp53tm1Tyj/+ Animals were of mixed background (80% C57BL/6, 20% "129/Sv") or N1 generation FVB backcross (50% FVB, 40% C57BL/6)(sic).

Models
Strain Model Name Treatment Agent(s) Organ Affected Frequency Model Details
[not specified]-Tg(Tyr-HRAS)60Lc Trp53tm1Tyj Leukocyte - Lymphocyte lymphoma Leukocyte - Lymphocyte

observed
[not specified]-Tg(Tyr-HRAS)60Lc Trp53tm1Tyj Mesodermal cell/mesoblast sarcoma Mesodermal cell/mesoblast

observed
[not specified]-Tg(Tyr-HRAS)60Lc Trp53tm1Tyj/+ Skin - Melanocyte melanoma Skin - Melanocyte

12
[not specified]-Tg(Tyr-HRAS)60Lc Trp53tm1Tyj Skin - Melanocyte melanoma Skin - Melanocyte

26
STOCK Tg(Tyr-HRAS)60Lc Skin - Melanocyte melanoma Skin - Melanocyte

0
[not specified]-Cdkn2atm1Rdp Tg(Tyr-HRAS)60Lc Skin - Melanocyte melanoma Skin - Melanocyte

observed