Dissection of melanogenesis with small molecules identifies prohibitin as a regulator.
Bioactive compounds can be used to selectively modulate gene function. We utilized a chemical genetic approach to dissect the mammalian pigmentation pathway and identify protein regulators. We screened a tagged library of 1170 small molecules in a cell-based assay and discovered a class of pigment-enhancing chemicals. From this class we characterized the small molecule melanogenin. Using melanogenin bound to an affinity matrix and amino acid sequencing, we identified the mitochondrial protein, prohibitin, as an intracellular binding target. Studies employing siRNA demonstrate that prohibitin is required for melanogenin to exert its propigmentary effects and reveal an unsuspected functional role for this protein in melanin induction. This represents a mechanism by which propigmentary signals are transduced and ultimately provides a potential target for the treatment of pigmentary disorders.
Snyder
Jane R
JR
The Ronald O. Perelman Department of Dermatology, New York University, New York 10016, USA.
Hall
Andrea
A
Ni-Komatsu
Li
L
Khersonsky
Sonya M
SM
Chang
Young-Tae
YT
Orlow
Seth J
SJ
D000595:Amino Acid Sequence; D015153:Blotting, Western; D002478:Cells, Cultured; D002846:Chromatography, Affinity; D004353:Drug Evaluation, Preclinical; D004591:Electrophoresis, Polyacrylamide Gel; D005455:Fluorescent Antibody Technique; D006801:Humans; D008543:Melanins / Q000096:biosynthesis*; D008544:Melanocytes / Q000187:drug effects / Q000378:metabolism; D008969:Molecular Sequence Data; D014442:Monophenol Monooxygenase / Q000378:metabolism; D010858:Pigmentation / Q000502:physiology; D000091402:Prohibitins; D011485:Protein Binding; D034741:RNA, Small Interfering / Q000378:metabolism; D012097:Repressor Proteins / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology; D014227:Triazines / Q000378:metabolism* / Q000494:pharmacology
D008543:Melanins; D000091402:Prohibitins; D034741:RNA, Small Interfering; D012097:Repressor Proteins; D014227:Triazines; C502970:melanogenin; D014442:Monophenol Monooxygenase