Cyclic AMP a key messenger in the regulation of skin pigmentation

Compelling evidence has been gathered indicating that proopiomelanocortin p eptides, alpha-melanocyte stimulating hormone (alpha-MSH) and adrenocortico tropic hormone (ACTH), through the cyclic AMP pathway, play a pivotal role in melanocyte differentiation and in the regulation of melanogenesis. Recen tly, the molecular events linking cAMP to melanogenesis up-regulation have been elucidated. This cascade involves the activation of protein kinase A a nd CREB transcription factor, leading to the up-regulation of the expressio n of Microphthalmia associated transcription factor (MITF). MITF has been f ound mutated in patients with Waardenbnrg syndrome 2A, and plays a crucial role in melanocyte development. MITF binds and activates melanogenic gene p romoters, thereby increasing their expression which results in an increased melanin synthesis. Beyond this simplified scheme. It appears that melanoge nic gene expression is controlled by a complex network of regulation involv ing other transcription factors such as Brn2, TBX2, PAX3 and SOX10. Further studies are required to better understand the respective roles of these fa ctors in the regulation of melanin synthesis. In addition, other intracellu lar signaling pathways, like the phosphatidyl inositol 3-kinase pathway, as well as the molecular cascade of events governed by the small GTP-binding protein Rho, seem to be involved in the regulation of melanogenesis and mel anocyte dendricity. Finally, it should be mentioned that cAMP activates a m elanocyte-specific pathway leading to MAP kinase activation. MAP kinase, ER K2, phosphorylates MITF, thereby targeting the transcription factor to prot easomes for degradation. Thus, in addition to the complex transcriptional r egulation, melanogenesis is also subjected to a post-translational regulati on that controls MITF or tyrosinase function. Taken together, these complex molecular processes mould finally allow a fine tuning of melanocyte differ entiation leading to melanin synthesis.