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MBC in Press, published online ahead of print October 16, 2002
Mol. Biol. Cell 10.1091/mbc.E02-05-0282

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Submitted on May 15, 2002
Revised on August 10, 2002
Accepted on August 29, 2002

The Pink-Eyed Dilution Protein Modulates Arsenic Sensitivity and Intracellular Glutathione Metabolism

Liliana Staleva1, Prashiela Manga1, and Seth J. Orlow1*

1 The Ronald O. Perelman Department of Dermatology and the Department of Cell Biology, New York University School of Medicine, New York, NY 10016, USA

* Corresponding author. E-mail address: seth.orlow{at}med.nyu.edu.

Mutations in the mouse p (pink-eyed dilution) and human P genes lead to melanosomal defects and ocular developmental abnormalities. Despite the critical role played by the p gene product in controlling tyrosinase processing and melanosome biogenesis, its precise biological function is still not defined. We have expressed p heterologously in the yeast Saccharomyces cerevisiae in order to study its function in greater detail. Immunofluorescence studies revealed that p reaches the yeast vacuolar membrane via the prevacuolar compartment. Yeast cells expressing p exhibited increased sensitivity to a number of toxic compounds, including arsenicals. Similarly, cultured murine melanocytes expressing a functional p gene were also found to be more sensitive to arsenical compounds compared to p-null cell lines. Intracellular glutathione, known to play a role in detoxification of arsenicals, was diminished by 50% in p-expressing yeast. By using the glutathione-conjugating dye monochlorobimane, in combination with acivicin, an inhibitor of vacuolar gamma glutamyl cysteine transpeptidase, involved in the breakdown of glutathione, we found that p facilitates the vacuolar accumulation of glutathione. Our data demonstrate that the pink eyed-dilution protein increases cellular sensitivity to arsenicals and other metalloids and can modulate intracellular glutathione metabolism.




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