Bertolotto C, Abbe P, Hemesath T J, Bille K, Fisher D E, Ortonne J P, Ballotti R
Institut National de la Sante et de la Recherche Medicale U385, Biologie et Physiopathologie de la Peau, Faculté de Médecine, Paris, France.
J Cell Biol. 1998 Aug 10;142(3):827-35. doi: 10.1083/jcb.142.3.827.
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.
黑素细胞分化的特征是黑素生成增加，它受到α-黑素细胞刺激激素通过激活cAMP途径的刺激。在此过程中，控制黑色素合成的酪氨酸酶的表达上调。我们之前表明，cAMP通过一个CATGTG基序调节酪氨酸酶基因的转录，该基序与小眼畸形相关转录因子结合，后者参与黑素细胞存活。此外，小眼畸形刺激酪氨酸酶启动子的转录活性，而cAMP增加小眼畸形与CATGTG基序的结合。这些观察结果使我们推测小眼畸形介导了cAMP对酪氨酸酶表达的影响。本研究旨在阐明cAMP调节小眼畸形功能的机制，并证明我们之前的假设，即小眼畸形是cAMP诱导的黑素生成的关键组成部分。首先，我们表明cAMP通过一个仅在黑素细胞中起作用的经典cAMP反应元件上调小眼畸形基因的转录。然后，使用小眼畸形的显性负性突变体，我们证明小眼畸形是cAMP对酪氨酸酶启动子产生作用所必需的。这些发现揭示了cAMP刺激酪氨酸酶表达和黑素生成的机制，并强调了小眼畸形作为cAMP诱导的黑素生成和色素细胞分化中信号转导器的关键作用。
