1. Identification of Novel Pigmentation Modulators by Chemical Genetic Screening
- Author
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Seth J. Orlow and Li Ni-Komatsu
- Subjects
Scaffold protein ,Skin Pigmentation ,Dermatology ,Biology ,Biochemistry ,03 medical and health sciences ,Mice ,0302 clinical medicine ,Prohibitins ,Animals ,Humans ,Genetic Testing ,Prohibitin ,Zebrafish ,Molecular Biology ,030304 developmental biology ,Genetics ,Melanins ,0303 health sciences ,Effector ,Mechanism (biology) ,Triazines ,Cell Biology ,Mitochondrial Proton-Translocating ATPases ,biology.organism_classification ,Small molecule ,3. Good health ,Cell biology ,Repressor Proteins ,030220 oncology & carcinogenesis ,Melanocytes ,Identification (biology) ,Linker ,Pigmentation Disorders - Abstract
There is a continual need for compounds that effectively modulate melanin synthesis. To identify novel pigmentation modulators and their cellular targets, chemical genetic screenings were performed with triazine-based combinatorial libraries that include various linkers as intrinsic components of the small molecules in the library. The linker provides a ready means of attachment to beads, eliminating several common time-consuming downstream steps in the isolation of cellular targets for the small molecules of interest. Twelve compounds were identified as novel pigmentation modulators from various screenings performed in normal and albino murine melanocytes and zebrafish. Target identification by affinity chromatography revealed unexpected roles for prohibitin and mitochondrial F1F0-adenotriphosphatase in the regulation of mammalian pigmentation. The identification of prohibitin, a "scaffold protein", as a propigmentation effector represents a novel mechanism by which propigmentary signals are transduced. Results from our screenings provide potential active agents and targets for the medical and aesthetic treatment of disorders of pigmentation.
- Published
- 2007
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