Tyrosinase-related proteins suppress tyrosinase-mediated cell death of melanocytes and melanoma cells

• Published in: Experimental cell research 2004-08, Vol.298 (2), p.317-328
• Main Authors: Rad, Hesamaddin Hejazy, Yamashita, Toshiharu, Jin, Hai-Ying, Hirosaki, Kuninori, Wakamatsu, Kazumasa, Ito, Shosuke, Jimbow, Kowichi
• Format: Article
• Language: English
• Subjects: Cell death; Cell Death - genetics; Cell Line, Tumor; Down-Regulation - genetics; Eumelanin; Free Radicals - metabolism; Gene Expression Regulation, Enzymologic - genetics; Gene Expression Regulation, Neoplastic - genetics; Gene Transfer Techniques; Genetic Vectors - genetics; Humans; Intramolecular Oxidoreductases - genetics; Intramolecular Oxidoreductases - metabolism; Melanins - biosynthesis; Melanocytes - cytology; Melanocytes - drug effects; Melanocytes - enzymology; Melanogenesis; Melanoma - enzymology; Melanoma - genetics; Melanoma cell lines; Membrane Glycoproteins - genetics; Membrane Glycoproteins - metabolism; Monophenol Monooxygenase - genetics; Monophenol Monooxygenase - metabolism; Oxidoreductases - genetics; Oxidoreductases - metabolism; Pheomelanin; Tyrosinase; Tyrosinase-related proteins; Up-Regulation - genetics
• ISSN: 0014-4827; 1090-2422
• DOI: 10.1016/j.yexcr.2004.04.045

The synthesis of melanin intermediates through tyrosinase (TYR) involves the production of cytotoxic free radicals. By using recombinant adenoviruses that express TYR, tyrosinase-related protein 1 (TYRP1) or DOPAchrome tautomerase (DCT), we analyzed the biological function of these proteins with regard to melanin production and the growth of melanocytes, fibroblasts, melanoma cells and nonmelanoma cancer cells. High-level expression of TYR produced newly synthesized melanin and induced cell death in all of these cells. However, when TYRP1 or DCT was coexpressed with TYR in melanocytes and melanoma cells, TYR-mediated cell death was clearly decreased. This decrease was not observed in nonmelanocytic cells. Western blot analysis and measurement of enzyme activity revealed that the expression of TYRP1 or DCT had little effect on the amount or activity of cointroduced TYR in either the melanocytic or nonmelanocytic cells. In cells expressing both TYR and TYRP1 or TYR and DCT, the total amount of melanin and/or eumelanin increased substantially more than that in cells expressing TYR alone. On the other hand, the level of pheomelanin was similar in these three cell types. These findings suggest that TYRP1 and DCT play an important role in suppressing TYR-mediated cytotoxicity in melanocytic cells without decreasing TYR expression and/or activity. These biological activities of TYRP1 and DCT may work through the interaction with TYR in melanosomal compartment.