Accumulation of tyrosinase in the endolysosomal compartment is induced by U18666A.
The 3beta-(2-diethylaminoethoxy)-androstenone HCl (U18666A), progesterone and several cationic amphiphilic drugs have been shown to alter the trafficking of a number of intracellular membrane proteins including CD63/Lamp-3, insulin growth factor 2/mannose 6-phosphate receptor (IGF2/MPR), and the Niemann-Pick C1 gene product (NPC1) as well as ganglioside GM1. We have examined the effects of these compounds on cultured melanocytes at concentrations that have been shown to effectively alter intracellular trafficking. Treatment of melanocytes with U18666A (2.5 micro M) or progesterone (15 micro M) for 96 h decreased melanin content an average of 67% as compared with control without lowering the total cellular tyrosinase activity. Steroidal alkaloids that preferentially act on the Sonic Hedgehog signaling pathway showed no related specificity in their ability to decrease pigmentation. In melanocytes treated with U18666A, tyrosinase accumulates in a compartment that contains both lysosome-associated membrane protein-1 (Lamp 1) and MPR, and stains with filipin, consistent with cholesterol-laden late endosomes/lysosomes. Our results suggest that tyrosinase, like the NPC1 gene product, traverses a U18666A-sensitive trafficking pathway.
Hall
Andrea M
AM
The Ronald O. Perelman Department of Dermatology, New York University School of Medicine, New York, NY, USA.
Krishnamoorthy
Lalitha
L
Orlow
Seth J
SJ
D000736:Androstenes / Q000494:pharmacology; D000818:Animals; D015703:Antigens, CD / Q000187:drug effects / Q000378:metabolism; D002352:Carrier Proteins / Q000187:drug effects / Q000378:metabolism; D002451:Cell Compartmentation / Q000187:drug effects* / Q000502:physiology; D002461:Cell Line, Transformed; D002784:Cholesterol / Q000378:metabolism; D011992:Endosomes / Q000187:drug effects / Q000201:enzymology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D000078404:Epidermal Cells; D004817:Epidermis / Q000187:drug effects* / Q000201:enzymology*; D005372:Filipin; D047908:Intracellular Signaling Peptides and Proteins; D037181:Lectins, C-Type / Q000187:drug effects / Q000378:metabolism; D051907:Lysosomal Membrane Proteins; D008247:Lysosomes / Q000187:drug effects / Q000201:enzymology*; D000090323:Mannose Receptor; D037241:Mannose-Binding Lectins / Q000187:drug effects / Q000378:metabolism; D008544:Melanocytes / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology*; D008562:Membrane Glycoproteins / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D014442:Monophenol Monooxygenase / Q000187:drug effects* / Q000378:metabolism; D000077296:Niemann-Pick C1 Protein; D011374:Progesterone / Q000494:pharmacology; D021381:Protein Transport / Q000187:drug effects / Q000502:physiology; D011956:Receptors, Cell Surface / Q000187:drug effects / Q000378:metabolism
D000736:Androstenes; D015703:Antigens, CD; D002352:Carrier Proteins; D004791:Enzyme Inhibitors; D047908:Intracellular Signaling Peptides and Proteins; D037181:Lectins, C-Type; D051907:Lysosomal Membrane Proteins; D000090323:Mannose Receptor; D037241:Mannose-Binding Lectins; D008562:Membrane Glycoproteins; C106881:NPC1 protein, human; D000077296:Niemann-Pick C1 Protein; D011956:Receptors, Cell Surface; C006261:3-beta-(2-(diethylamino)ethoxy)androst-5-en-17-one; D011374:Progesterone; D005372:Filipin; D002784:Cholesterol; D014442:Monophenol Monooxygenase