Melanoma mouse model implicates metabotropic glutamate signaling in melanocytic neoplasia.
To gain insight into melanoma pathogenesis, we characterized an insertional mouse mutant, TG3, that is predisposed to develop multiple melanomas. Physical mapping identified multiple tandem insertions of the transgene into intron 3 of Grm1 (encoding metabotropic glutamate receptor 1) with concomitant deletion of 70 kb of intronic sequence. To assess whether this insertional mutagenesis event results in alteration of transcriptional regulation, we analyzed Grm1 and two flanking genes for aberrant expression in melanomas from TG3 mice. We observed aberrant expression of only Grm1. Although we did not detect its expression in normal mouse melanocytes, Grm1 was ectopically expressed in the melanomas from TG3 mice. To confirm the involvement of Grm1 in melanocytic neoplasia, we created an additional transgenic line with Grm1 expression driven by the dopachrome tautomerase promoter. Similar to the original TG3, the Tg(Grm1)EPv line was susceptible to melanoma. In contrast to human melanoma, these transgenic mice had a generalized hyperproliferation of melanocytes with limited transformation to fully malignant metastasis. We detected expression of GRM1 in a number of human melanoma biopsies and cell lines but not in benign nevi and melanocytes. This study provides compelling evidence for the importance of metabotropic glutamate signaling in melanocytic neoplasia.
Pollock
Pamela M
PM
Cancer Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
Cohen-Solal
Karine
K
Sood
Raman
R
Namkoong
Jin
J
Martino
Jeffrey J
JJ
Koganti
Aruna
A
Zhu
Hua
H
Robbins
Christiane
C
Makalowska
Izabela
I
Shin
Seung-Shick
SS
Marin
Yari
Y
Roberts
Kathleen G
KG
Yudt
Laura M
LM
Chen
Amy
A
Cheng
Jun
J
Incao
Arturo
A
Pinkett
Heather W
HW
Graham
Christopher L
CL
Dunn
Karen
K
Crespo-Carbone
Steven M
SM
Mackason
Kerine R
KR
Ryan
Kevin B
KB
Sinsimer
Daniel
D
Goydos
James
J
Reuhl
Kenneth R
KR
Eckhaus
Michael
M
Meltzer
Paul S
PS
Pavan
William J
WJ
Trent
Jeffrey M
JM
Chen
Suzie
S
D000818:Animals; D018076:DNA, Complementary / Q000235:genetics; D004273:DNA, Neoplasm / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D008545:Melanoma / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D016254:Mutagenesis, Insertional; D018094:Receptors, Metabotropic Glutamate / Q000235:genetics* / Q000378:metabolism*; D015398:Signal Transduction; D012878:Skin Neoplasms / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D014162:Transfection
D018076:DNA, Complementary; D004273:DNA, Neoplasm; D018094:Receptors, Metabotropic Glutamate