Control of melanocyte differentiation by a MITF-PDE4D3 homeostatic circuit.
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.
Department of Dermatology, Cutaneous Biology Research Center, Massachusetts General Hospital, Harvard Medical School, Massachusetts 02114, USA.
Mehdi
M
Khaled
Carmit
C
Levy
David E
DE
Fisher
D000818:Animals; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4 / Q000235:genetics / Q000378:metabolism*; D025461:Feedback, Physiological; D006706:Homeostasis; D006801:Humans; D015151:Immunoblotting; D007231:Infant, Newborn; D008297:Male; D008543:Melanins / Q000378:metabolism; D009074:Melanocyte-Stimulating Hormones / Q000235:genetics / Q000378:metabolism; D008544:Melanocytes / Q000166:cytology / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D051739:Microphthalmia-Associated Transcription Factor / Q000235:genetics / Q000378:metabolism*; D058988:Phosphodiesterase 4 Inhibitors; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D011485:Protein Binding; D034622:RNA Interference; D020889:Rolipram / Q000494:pharmacology; D015398:Signal Transduction; D012867:Skin / Q000187:drug effects / Q000378:metabolism
D008543:Melanins; D051739:Microphthalmia-Associated Transcription Factor; D058988:Phosphodiesterase 4 Inhibitors; D010726:Phosphodiesterase Inhibitors; D005576:Colforsin; D009074:Melanocyte-Stimulating Hormones; D000242:Cyclic AMP; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D020889:Rolipram