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.
Khaled
Mehdi
M
Department of Dermatology, Cutaneous Biology Research Center, Massachusetts General Hospital, Harvard Medical School, Massachusetts 02114, USA.
Levy
Carmit
C
Fisher
David E
DE
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