title: Glycogen synthase kinase 3beta is activated by cAMP and plays an active role in the regulation of melanogenesis.
abstract: In human and mouse, cAMP plays a key role in the control of pigmentation. cAMP, through the activation of protein kinase A, increases the expression of microphthalmia-associated transcription factor (MITF), which in turn stimulates tyrosinase gene expression, to allow melanin synthesis. Beyond this simplified scheme, cAMP inhibits phosphatidylinositol 3-kinase (PI3K), and inhibition of PI3K, by a specific inhibitor, stimulates melanogenesis. However, the link between the PI3K pathway and melanogenesis remained to be elucidated. In this report, we showed that cAMP, through a protein kinase A-independent mechanism, led to inhibition of AKT phosphorylation and activity. Consistent with the role of AKT in the regulation of glycogen synthase kinase 3beta (GSK3beta), cAMP decreased the phosphorylation of GSK3beta and stimulated its activity. Further, experiments were performed to investigate the role of GSK3beta in the regulation of MITF expression and function. We observed that GSK3beta regulated neither MITF promoter activity nor the intrinsic transcriptional activity of MITF but synergized with MITF to activate the tyrosinase promoter. Additionally, lithium, a GSK3beta inhibitor, impaired the response of the tyrosinase promoter to cAMP, and cAMP increased the binding of MITF to the M-box. Taking into account that GSK3beta phosphorylates MITF and increases the ability of MITF to bind its target sequence, our results indicate that activation of GSK3beta by cAMP facilitates MITF binding to the tyrosinase promoter, thereby leading to stimulation of melanogenesis.
authors.affiliation: INSERM U385, Biologie et Physiopathologie de la peau, IFR 50, 28 avenue de Valombrose, 06107 NICE Cedex 2, France.
authors.forename: Mehdi
authors.initials: M
authors.lastname: Khaled
authors.forename: Lionel
authors.initials: L
authors.lastname: Larribere
authors.forename: Karine
authors.initials: K
authors.lastname: Bille
authors.forename: Edith
authors.initials: E
authors.lastname: Aberdam
authors.forename: Jean-Paul
authors.initials: JP
authors.lastname: Ortonne
authors.forename: Robert
authors.initials: R
authors.lastname: Ballotti
authors.forename: Corine
authors.initials: C
authors.lastname: Bertolotto
mesh_terms: D000818:Animals; D000242:Cyclic AMP / Q000502:physiology*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000502:physiology; D004268:DNA-Binding Proteins / Q000378:metabolism; D004789:Enzyme Activation; D038362:Glycogen Synthase Kinase 3 / Q000502:physiology*; D000071679:Glycogen Synthase Kinase 3 beta; D008543:Melanins / Q000096:biosynthesis*; D051379:Mice; D051739:Microphthalmia-Associated Transcription Factor; D020928:Mitogen-Activated Protein Kinases / Q000502:physiology; D014442:Monophenol Monooxygenase / Q000235:genetics; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D014157:Transcription Factors / Q000378:metabolism; D014407:Tumor Cells, Cultured
chemical_list: D004268:DNA-Binding Proteins; D008543:Melanins; D051739:Microphthalmia-Associated Transcription Factor; C497235:Mitf protein, mouse; D011518:Proto-Oncogene Proteins; D014157:Transcription Factors; D000242:Cyclic AMP; D014442:Monophenol Monooxygenase; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D017868:Cyclic AMP-Dependent Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D038362:Glycogen Synthase Kinase 3