title: MC1R and cAMP signaling inhibit cdc25B activity and delay cell cycle progression in melanoma cells.
abstract: The melanocortin 1 receptor (MC1R) mediates the tanning response through induction of cAMP and downstream pigmentary enzymes. Diminished function alleles of MC1R are associated with decreased tanning and increased melanoma risk, which has been attributed to increased rates of mutation. We have found that MC1R or cAMP signaling also directly decreases proliferation in melanoma cell lines. MC1R overexpression, treatment with the MC1R ligand, or treatment with small-molecule activators of cAMP signaling causes delayed progression from G2 into mitosis. This delay is caused by phosphorylation and inhibition of cdc25B, a cyclin dependent kinase 1-activating phosphatase, and is rescued by expression of a cdc25B mutant that cannot be phosphorylated at the serine 323 residue. These results show that MC1R and cAMP signaling can directly inhibit melanoma growth through regulation of the G2/M checkpoint.
authors.affiliation: Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, CA 94115, USA.
authors.forename: Jesse
authors.initials: J
authors.lastname: Lyons
authors.forename: Boris C
authors.initials: BC
authors.lastname: Bastian
authors.forename: Frank
authors.initials: F
authors.lastname: McCormick
mesh_terms: D015153:Blotting, Western; D045744:Cell Line, Tumor; D000242:Cyclic AMP / Q000378:metabolism*; D005434:Flow Cytometry; D059565:G2 Phase Cell Cycle Checkpoints / Q000502:physiology*; D006801:Humans; D008545:Melanoma / Q000503:physiopathology*; D044102:Receptor, Melanocortin, Type 1 / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D020687:cdc25 Phosphatases / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: D044102:Receptor, Melanocortin, Type 1; D000242:Cyclic AMP; C517008:CDC25B protein, human; D020687:cdc25 Phosphatases
keywords: g-protein coupled receptors; genetic risk factors; skin cancer
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