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© The Rockefeller University Press, 0021-9525/1998//827 $5.00
The Journal of Cell Biology, Volume 142, Number 3, , 1998 827-835

Microphthalmia Gene Product as a Signal Transducer in cAMP-Induced Differentiation of Melanocytes

Corine Bertolotto, Patricia Abbe, Timothy J. Hemesath^*, Karine Bille, David E. Fisher^*, Jean-Paul Ortonne, and Robert Ballotti

^* Division of Pediatric Hematology/Oncology, Children's Hospital and Dana Farber Cancer Institute, Harvard Medical School, Boston, Massachussets 02115; Institut National de la Sante et de la Recherche Medicale U385, Biologie et Physiopathologie de la Peau, Faculté de Médecine, Paris, France

Melanocyte differentiation characterized by an increased melanogenesis, is stimulated by -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.

Key Words: melanocytes • cAMP • microphthalmia • tyrosinase • differentiation

Abbreviations used in this paper: -MSH, -melanocyte–stimulating hormone; b-HLH, basic-helix-loop-helix; CREB, cAMP response element binding protein; CBP, CREB binding protein; Fsk, forskolin; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; Mi, microphthalmia; MITF, microphthalmia-associated transcription factor; PKA, protein kinase A; pNPP, paranitro-phenylphosphate; TRP1 and TRP2, tyrosinase-related proteins 1 and 2.

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