Wnt/β-catenin signaling is stimulated by α-melanocyte-stimulating hormone in melanoma and melanocyte cells: implication in cell differentiation.
Wnt/β-catenin signaling plays important roles in many developmental processes including neural crest-derived melanocyte development and migration. However, the effective contribution of Wnt/β-catenin pathway in melanogenesis in adult human melanocytes has not been fully elucidated. Here, we report that in melanoma cells and in normal human melanocytes, melanogenesis stimulation by α-melanocyte-stimulating hormone (α-MSH) induces phosphorylation of β-catenin-Ser675 and stabilization of β-catenin protein. Activation of protein kinase A by α-MSH attenuates glycogen synthase kinase-3β, which regulates ubiquitin-dependent degradation of β-catenin, suggesting a coordinated mechanism of β-catenin activity stimulation. Consistent with increased nuclear β-catenin, cyclic adenosine monophosphate (cAMP) elevation facilitates β-catenin-dependent transactivation of many Wnt target genes. Moreover, chromatin immunoprecipitation assays demonstrated an increased association of β-catenin with the proximal promoter of microphthalmia-associated transcription factor, the master regulator of pigmentation. These results demonstrate the existence of cross talk between the cAMP and Wnt pathways in melanocytes, suggesting that β-catenin could play a key role in the physiological regulation of epidermal melanogenesis.
Laboratory of Cutaneous Physiopatology, San Gallicano Dermatologic Institute, IRCCS, Rome, Italy. bellei@ifo.it
Barbara
B
Bellei
Angela
A
Pitisci
Caterina
C
Catricalà
Lionel
L
Larue
Mauro
M
Picardo
D000328:Adult; D000818:Animals; D002454:Cell Differentiation / Q000502:physiology*; D045744:Cell Line, Tumor; D000242:Cyclic AMP / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D008543:Melanins / Q000096:biosynthesis; D008544:Melanocytes / Q000166:cytology / Q000378:metabolism*; D008545:Melanoma / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D051739:Microphthalmia-Associated Transcription Factor / Q000378:metabolism; D014442:Monophenol Monooxygenase / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D014158:Transcription, Genetic; D051153:Wnt Proteins / Q000378:metabolism*; D000521:alpha-MSH / Q000378:metabolism*; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism*
D008543:Melanins; D051739:Microphthalmia-Associated Transcription Factor; D034741:RNA, Small Interfering; D051153:Wnt Proteins; D051176:beta Catenin; D000521:alpha-MSH; D000242:Cyclic AMP; D014442:Monophenol Monooxygenase