Abstract
Cyclic AMP (cAMP) is a ubiquitous second messenger that regulates a variety of biological processes. The magnitude and duration of cAMP expression are regulated by both production and hydrolysis. Melanocyte-stimulating hormone (MSH) plays a crucial role in pigment cell differentiation via cAMP-regulated expression of the master transcription factor MITF. We report the identification of phosphodiesterase 4D3 as a direct target of the MSH/cAMP/MITF pathway. This creates a negative feedback loop that induces refractoriness to chronic stimulation of the cAMP pathway in melanocytes. This homeostatic pathway highlights a potent mechanism controlling melanocyte differentiation that may be amenable to pharmacologic manipulation for skin cancer prevention.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
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Animals
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Cell Differentiation*
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Cell Line, Tumor
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Cells, Cultured
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Colforsin / pharmacology
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Cyclic AMP / metabolism
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Cyclic Nucleotide Phosphodiesterases, Type 4 / genetics
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Cyclic Nucleotide Phosphodiesterases, Type 4 / metabolism*
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Feedback, Physiological
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Homeostasis
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Humans
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Immunoblotting
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Infant, Newborn
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Male
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Melanins / metabolism
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Melanocyte-Stimulating Hormones / genetics
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Melanocyte-Stimulating Hormones / metabolism
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Melanocytes / cytology
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Melanocytes / metabolism*
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Mice
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Mice, Inbred C57BL
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Microphthalmia-Associated Transcription Factor / genetics
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Microphthalmia-Associated Transcription Factor / metabolism*
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Phosphodiesterase 4 Inhibitors
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Phosphodiesterase Inhibitors / pharmacology
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Protein Binding
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RNA Interference
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Rolipram / pharmacology
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Signal Transduction
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Skin / drug effects
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Skin / metabolism
Substances
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Melanins
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Microphthalmia-Associated Transcription Factor
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Phosphodiesterase 4 Inhibitors
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Phosphodiesterase Inhibitors
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Colforsin
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Melanocyte-Stimulating Hormones
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Cyclic AMP
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Cyclic Nucleotide Phosphodiesterases, Type 4
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Rolipram