MITOGEN-ACTIVATED PROTEIN-KINASE PATHWAY AND AP-1 ARE ACTIVATED DURING CAMP-INDUCED MELANOGENESIS IN B-16 MELANOMA-CELLS

In mammalian melanocytes, melanin synthesis is controlled by tyrosinas e, the critical enzyme in the melanogenic pathway. We and others showe d that the stimulation of melanogenesis by cAMP is due to an increased tyrosinase expression at protein and mRNA levels, However, the molecu lar events connecting the rise of intracellular cAMP and the increase in tyrosinase activity remain to be elucidated, In this study, using B 16 melanoma cells, we showed that cAMP-elevating agents stimulated mit ogen-activated protein (MAP) kinase, p44(mapk). This effect was mediat ed by the activation of MAP kinase kinase, cAMP-elevating agents induc ed a translocation of p44(mapk) to the nucleus and an activation of th e transcription factor AP-1, cAMP-induced AP-1 contained FOS-related a ntigen-2 in association with JunD, while after phorbol ester stimulati on AP-1 complexes consist mainly of JunD/c-Fos heterodimers. In an att empt to connect these molecular events to the control of tyrosinase ex pression that appears to be the pivotal point of melanogenesis regulat ion, we hypothesized that following its activation by cAMP, p44(mapk) activates AP-1, Then AP-1 could stimulate tyrosinase expression throug h the interaction with specific DNA sequences present in the mouse tyr osinase promoter.