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A more recent version of this article appeared on June 1, 2002
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Submitted on October 26, 2001
Revised on February 14, 2002
Accepted on February 25, 2002
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.
The processing of tyrosinase, which catalyzes the limiting reaction in melanin synthesis, was investigated in melan-p1 melanocytes, which are null at the p locus. Endoglycosidase H digestion showed that a significant fraction of tyrosinase was retained in the endoplasmic reticulum. This retention could be rescued either by transfection of melan-p1 cells with an epitope-tagged wildtype p transcript or by treatment with either bafilomycin A1 or ammonium chloride. We found that the endoplasmic reticulum contains a significant amount of p protein, thus supporting a role for p within this compartment. Using immunofluoresence, we showed that most mature full-length tyrosinase in melan-p1 cells was located in the perinuclear area near the Golgi, in contrast to its punctate melanosomal pattern in wildtype melanocytes. Expression of p in melan-p1 cells restored tyrosinase to melanosomes. Triton X-114 phase separation revealed that an increased amount of tyrosinase was proteolyzed in melan-p1 cells compared to wildtype melanocytes. The proteolyzed tyrosinase was no longer membrane bound, but remained enzymatically active and a large proportion was secreted into the culture medium of melan-p1 cells. We conclude that p regulates post-translational processing of tyrosinase and hypopigmentation in melan-p1 cells is the result of altered tyrosinase processing and trafficking.
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