Reference SummaryChin L, Genes Dev 1997 Nov 1;11(21):2822-34

Title

 Cooperative effects of INK4a and ras in melanoma susceptibility in vivo.

Authors

 Chin L; Pomerantz J; Polsky D; Jacobson M; Cohen C; Cordon-Cardo C; Horner JW 2nd; DePinho RA

Journal

 Genes Dev

Volume

 11

Issue

 21

Year

 1997

Pages

 2822-34

Abstract

 The familial melanoma gene (INK4a/MTS1/CDKN2) encodes potent tumor suppressor activity. Although mice null for the ink4a homolog develop a cancer-prone condition, a pathogenetic link to melanoma susceptibility has yet to be established. Here we report that mice with melanocyte-specific expression of activated H-rasG12V on an ink4a-deficient background develop spontaneous cutaneous melanomas after a short latency and with high penetrance. Consistent loss of the wild-type ink4a allele was observed in tumors arising in ink4a heterozygous transgenic mice. No homozygous deletion of the neighboring ink4b gene was detected. Moreover, as in human melanomas, the p53 gene remained in a wild-type configuration with no observed mutation or allelic loss. These results show that loss of ink4a and activation of Ras can cooperate to accelerate the development of melanoma and provide the first in vivo experimental evidence for a causal relationship between ink4a deficiency and the pathogenesis of melanoma. In addition, this mouse model affords a system in which to identify and analyze pathways involved in tumor progression against the backdrop of genetic alterations encountered in human melanomas.

Links

 J:44088 – MGI References
9353252 – National Library of Medicine/PubMed

Strain Notes

Strain Note
STOCK Cdkn2atm1Rdp These mice were generated using the WW6 ES cell line (75% 129/Sv, 20% C57BL/6, 5% SJL). Chimeric males were mated to C57BL/6 females. Offspring were then intercrossed to generate mice wild type, heterozygous, and homozygous for the mutant allele.
STOCK Cdkn2atm1Rdp Tg(Tyr-HRAS)60Lc The genetic background was described as C57BL/6J (65%), CBA/J (25%), "129/Sv" (9.4%), and SJL/J (0.6%).
STOCK Cdkn2atm1Rdp/+ Tg(Tyr-HRAS)60Lc The genetic background was described as C57BL/6J (65%), CBA/J (25%), "129/Sv" (9.4%), and SJL/J (0.6%).
STOCK Cdkn2atm1Rdp Tg(Tyr-HRAS)#Lc The genetic background was described as C57BL/6 (65%), CBA (25%) and "129/Sv" (10%).
STOCK Cdkn2atm1Rdp/+ Tg(Tyr-HRAS)#Lc The genetic background was described as C57BL/6 (65%), CBA (25%) and "129/Sv" (10%).
STOCK Tg(Tyr-HRAS)60Lc The genetic background was described as C57BL/6J (65%), CBA/J (25%), "129/Sv" (9.4%), and SJL/J (0.6%).
Transgenic mice expressing activated human HRAS (G12V) in melanocytes.

Models
Strain Model Name Treatment Agent(s) Organ Affected Frequency Model Details
STOCK Cdkn2atm1Rdp Tg(Tyr-HRAS)60Lc Connective tissue - Fibroblast fibrosarcoma Connective tissue - Fibroblast

18
STOCK Cdkn2atm1Rdp Skin - Melanocyte melanoma Skin - Melanocyte

0
STOCK Cdkn2atm1Rdp/+ Skin - Melanocyte melanoma Skin - Melanocyte

0
STOCK Cdkn2atm1Rdp/+ Tg(Tyr-HRAS)#Lc Skin - Melanocyte melanoma Skin - Melanocyte

observed
STOCK Cdkn2atm1Rdp Tg(Tyr-HRAS)#Lc Skin - Melanocyte melanoma Skin - Melanocyte

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

2.4
STOCK Cdkn2atm1Rdp/+ Tg(Tyr-HRAS)60Lc Skin - Melanocyte melanoma Skin - Melanocyte

4
STOCK Cdkn2atm1Rdp Tg(Tyr-HRAS)60Lc Skin - Melanocyte melanoma Skin - Melanocyte

81