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Proc Natl Acad Sci U S A. 2009 Feb 10;106(6):1802-7. Epub 2009 Jan 27.
Microarray analysis sheds light on the dedifferentiating role of agouti
signal protein in murine melanocytes via the Mc1r.
Le Pape E, Passeron T, Giubellino A, Valencia JC, Wolber R, Hearing VJ.
Pigment Cell Biology Section, Laboratory of Cell Biology, National
Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
The melanocortin-1 receptor (MC1R) is a key regulator of pigmentation in
mammals and is tightly linked to an increased risk of skin cancers,
including melanoma, in humans. Physiologically activated by
alpha-melanocyte stimulating hormone (alphaMSH), MC1R function can be
antagonized by a secreted factor, agouti signal protein (ASP), which is
responsible for the lighter phenotypes in mammals (including humans),
and is also associated with increased risk of skin cancer. It is
therefore of great interest to characterize the molecular effects
elicited by those MC1R ligands. In this study, we determined the gene
expression profiles of murine melan-a melanocytes treated with ASP or
alphaMSH over a 4-day time course using genome-wide oligonucleotide
microarrays. As expected, there were significant reductions in
expression of numerous melanogenic proteins elicited by ASP, which
correlates with its inhibition of pigmentation. ASP also unexpectedly
modulated the expression of genes involved in various other cellular
pathways, including glutathione synthesis and redox metabolism. Many
genes up-regulated by ASP are involved in morphogenesis (especially in
nervous system development), cell adhesion, and extracellular
matrix-receptor interactions. Concomitantly, ASP enhanced the migratory
potential and the invasiveness of melanocytic cells in vitro. These
results demonstrate the role of ASP in the dedifferentiation of
melanocytes, identify pigment-related genes targeted by ASP and by
alphaMSH, and provide insights into the pleiotropic molecular effects of
MC1R signaling that may function during development and may affect skin
cancer risk.
Publication Types:
* Research Support, N.I.H., Intramural
PMID: 19174519 |
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