Microphthalmia gene product as a signal transducer in cAMP-induced differentiation of melanocytes.
Melanocyte differentiation characterized by an increased melanogenesis, is stimulated by alpha-melanocyte-stimulating hormone through activation of the cAMP pathway. During this process, the expression of tyrosinase, the enzyme that controls melanin synthesis is upregulated. We previously showed that cAMP regulates transcription of the tyrosinase gene through a CATGTG motif that binds microphthalmia a transcription factor involved in melanocyte survival. Further, microphthalmia stimulates the transcriptional activity of the tyrosinase promoter and cAMP increases the binding of microphthalmia to the CATGTG motif. These observations led us to hypothesize that microphthalmia mediates the effect of cAMP on the expression of tyrosinase. The present study was designed to elucidate the mechanism by which cAMP regulates microphthalmia function and to prove our former hypothesis, suggesting that microphthalmia is a key component in cAMP-induced melanogenesis. First, we showed that cAMP upregulates the transcription of microphthalmia gene through a classical cAMP response element that is functional only in melanocytes. Then, using a dominant-negative mutant of microphthalmia, we demonstrated that microphthalmia is required for the cAMP effect on tyrosinase promoter. These findings disclose the mechanism by which cAMP stimulates tyrosinase expression and melanogenesis and emphasize the critical role of microphthalmia as signal transducer in cAMP-induced melanogenesis and pigment cell differentiation.
Institut National de la Sante et de la Recherche Medicale U385, Biologie et Physiopathologie de la Peau, Faculté de Médecine, Paris, France.
C
C
Bertolotto
P
P
Abbe
T J
TJ
Hemesath
K
K
Bille
D E
DE
Fisher
J P
JP
Ortonne
R
R
Ballotti
D016475:3T3 Cells; D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects; D000242:Cyclic AMP / Q000502:physiology*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000502:physiology*; D004789:Enzyme Activation; D005786:Gene Expression Regulation; D005809:Genes, Regulator; D006801:Humans; D008544:Melanocytes / Q000166:cytology*; D008546:Melanoma, Experimental; D051379:Mice; D051739:Microphthalmia-Associated Transcription Factor; D014442:Monophenol Monooxygenase / Q000235:genetics; D011401:Promoter Regions, Genetic / Q000187:drug effects; D015398:Signal Transduction; D014157:Transcription Factors; D014158:Transcription, Genetic / Q000187:drug effects; D014407:Tumor Cells, Cultured
D004268:DNA-Binding Proteins; C497234:MITF protein, human; D051739:Microphthalmia-Associated Transcription Factor; C497235:Mitf protein, mouse; D014157:Transcription Factors; D000242:Cyclic AMP; D014442:Monophenol Monooxygenase