Cooperative effects of INK4a and ras in melanoma susceptibility in vivo.
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.
Chin
L
L
Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, New York 10461, USA.
Pomerantz
J
J
Polsky
D
D
Jacobson
M
M
Cohen
C
C
Cordon-Cardo
C
C
Horner
J W
JW
DePinho
R A
RA
D000818:Animals; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics*; D017931:DNA Primers; D004198:Disease Susceptibility; D005091:Exons; D005134:Eye Neoplasms / Q000235:genetics* / Q000473:pathology; D019942:Genes, p16; D011905:Genes, ras; D006801:Humans; D008545:Melanoma / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D016133:Polymerase Chain Reaction; D012878:Skin Neoplasms / Q000235:genetics* / Q000473:pathology
D019941:Cyclin-Dependent Kinase Inhibitor p16; D017931:DNA Primers