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J. Cell Biol.,
Volume 142, Number 3, August 10, 1998 827-835
* Division of Pediatric Hematology/Oncology, Children's Hospital and Dana Farber Cancer Institute, Harvard Medical School,
Boston, Massachussets 02115; Melanocyte differentiation characterized by
an increased melanogenesis, is stimulated by Institut National de la Sante et de la Recherche Medicale U385, Biologie et Physiopathologie de
la Peau, Faculté de Médecine, Paris, France
-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.
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