Abstract
In mammalian melanocytes, melanin synthesis is controlled by tyrosinase, the critical enzyme in the melanogenic pathway. We and others showed that the stimulation of melanogenesis by cAMP is due to an increased tyrosinase expression at protein and mRNA levels. However, the molecular events connecting the rise of intracellular cAMP and the increase in tyrosinase activity remain to be elucidated. In this study, using B16 melanoma cells, we showed that cAMP-elevating agents stimulated mitogen-activated protein (MAP) kinase, p44mapk. This effect was mediated by the activation of MAP kinase kinase. cAMP-elevating agents induced a translocation of p44mapk to the nucleus and an activation of the transcription factor AP-1. cAMP-induced AP-1 contained FOS-related antigen-2 in association with JunD, while after phorbol ester stimulation AP-1 complexes consist mainly of JunD/c-Fos heterodimers. In an attempt to connect these molecular events to the control of tyrosinase expression that appears to be the pivotal point of melanogenesis regulation, we hypothesized that following its activation by cAMP, p44mapk activates AP-1. Then AP-1 could stimulate tyrosinase expression through the interaction with specific DNA sequences present in the mouse tyrosinase promoter.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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1-Methyl-3-isobutylxanthine / pharmacology*
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Affinity Labels
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Animals
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Calcium-Calmodulin-Dependent Protein Kinases / metabolism*
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Cell Nucleus / metabolism
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Cyclic AMP / metabolism*
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Enzyme Activation
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Gene Expression
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MAP Kinase Kinase Kinase 1*
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Melanins / biosynthesis*
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Melanoma, Experimental / metabolism*
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Mice
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Microscopy, Confocal
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Mitogen-Activated Protein Kinase Kinases
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Monophenol Monooxygenase / biosynthesis
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Monophenol Monooxygenase / metabolism*
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Phosphodiesterase Inhibitors / pharmacology
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Protein Kinases / metabolism
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Protein Serine-Threonine Kinases / analysis
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Protein Serine-Threonine Kinases / metabolism
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Proto-Oncogene Proteins / analysis
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Proto-Oncogene Proteins / metabolism
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Proto-Oncogene Proteins c-jun / metabolism
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Proto-Oncogene Proteins c-raf
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RNA, Messenger / biosynthesis
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RNA, Messenger / metabolism
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Tetradecanoylphorbol Acetate / pharmacology
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Transcription Factor AP-1 / metabolism*
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alpha-MSH / analogs & derivatives
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alpha-MSH / pharmacology
Substances
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Affinity Labels
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Melanins
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Phosphodiesterase Inhibitors
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Proto-Oncogene Proteins
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Proto-Oncogene Proteins c-jun
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RNA, Messenger
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Transcription Factor AP-1
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alpha-MSH
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MSH, 4-Nle-7-Phe-alpha-
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Cyclic AMP
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Monophenol Monooxygenase
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Protein Kinases
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Protein Serine-Threonine Kinases
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Proto-Oncogene Proteins c-raf
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Calcium-Calmodulin-Dependent Protein Kinases
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MAP Kinase Kinase Kinase 1
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Map3k1 protein, mouse
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Mitogen-Activated Protein Kinase Kinases
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Tetradecanoylphorbol Acetate
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1-Methyl-3-isobutylxanthine