Melanosomal Defects in Melanocytes from Mice Lacking Expression of thePink-Eyed DilutionGene: Correction by Culture in the Presence of Excess Tyrosine

Rosemblat, Susana; Sviderskaya, Elena V.; Easty, David J.; Wilson, Amanda J.; Kwon, Byoung S.; Bennett, Dorothy C.; Orlow, Seth J.

doi:10.1006/excr.1997.3901

Cited by 56 publications

(61 citation statements)

References 35 publications

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“…In fact, extracts of p-null melanocytes exhibit higher levels of both Tyr activity and protein than wild-type melanocytes ). In addition, we and others (Russell, 1949;Moyer, 1966;Rittenhouse, 1968;Rosemblat et al, 1998;Orlow and Brilliant, 1999) have observed defects in melanosomal structure that cannot be easily explained by the hypothesis that p serves as a melanosomal proton pump. We have also shown that the trafficking of melanosomal proteins was altered in p-null melanocytes , and Tyr is extensively secreted into the culture media after intracellular cleavage.…”

Section: Introductionmentioning

confidence: 66%

“…Thus, the effects of bafilomycin A1 on Tyr degradation in melan-p1 may be mediated through a reduction in cathepsin proteases. High tyrosine can also induce melan-p1 cells to produce melanin (Sviderskaya et al, 1997;Rosemblat et al, 1998). This is associated with an increase in the concentration of mature Tyr.…”

Section: Discussionmentioning

confidence: 99%

“…Hypotheses regarding p function include the following: 1) p transports tyrosine into melanosomes (Lee et al, 1995). 2) p plays a structural role in melanosomes (Donatien and Orlow, 1995;Rosemblat et al, 1998) or is involved in melanosome biogenesis (Orlow and Brilliant, 1999). 3) p plays a role as a pH regulator in melanosomes and provides an optimal pH for Tyr activity (Puri et al, 2000;Brilliant, 2001).…”

Section: Discussionmentioning

confidence: 99%

“…In contrast to oculocutaneous albinism type 1, which results from Tyr mutations, patients with OCA2 express active TYR (King et al, 1985). p was initially thought to be a melanosomal tyrosine transporter (Kugelman and Van Scott, 1968;Rinchik et al, 1993;Lee et al, 1995;Sviderskaya et al, 1997;Rosemblat et al, 1998). However, kinetic studies of tyrosine uptake showed that there was a functional tyrosine transporter system in melanosomes of p-null melanocytes, and no difference in the rate of tyrosine uptake was found between wild-type and p-null melanocytes (Gahl et al, 1995;Potterf et al, 1998).…”

Section: Introductionmentioning

confidence: 99%

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Pink-eyed Dilution Protein Controls the Processing of Tyrosinase

Chen

Manga

Orlow

2002

MBoC

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128

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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 wild-type 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 wild-type 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 with wild-type 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 posttranslational processing of tyrosinase, and hypopigmentation in melan-p1 cells is the result of altered tyrosinase processing and trafficking.

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Section: Introductionmentioning

confidence: 66%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Pink-eyed Dilution Protein Controls the Processing of Tyrosinase

Chen

Manga

Orlow

2002

MBoC

Self Cite

128

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“…Defects in the corresponding murine gene (p) give rise to the pink-eyed dilution mouse (Rinchik et al, 1993), which has similar eye and coat hypopigmentation. Melanocytes from this model mouse contain melanosomes that are small, immature, and hypopigmented relative to normal melanosomes (Sidman et al, 1965;Rosemblat et al, 1998). Although these features clearly implicate OCA2 as being critical for pigmentation, the molecular function of OCA2 is still unclear.…”

mentioning

confidence: 94%

Localization to Mature Melanosomes by Virtue of Cytoplasmic Dileucine Motifs Is Required for Human OCA2 Function

Sitaram

Piccirillo

Palmisano

et al. 2009

MBoC

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Oculocutaneous albinism type 2 is caused by defects in the gene OCA2, encoding a pigment cell-specific, 12-transmembrane domain protein with homology to ion permeases. The function of the OCA2 protein remains unknown, and its subcellular localization is under debate. Here, we show that endogenous OCA2 in melanocytic cells rapidly exits the endoplasmic reticulum (ER) and thus does not behave as a resident ER protein. Consistently, exogenously expressed OCA2 localizes within melanocytes to melanosomes, and, like other melanosomal proteins, localizes to lysosomes when expressed in nonpigment cells. Mutagenized OCA2 transgenes stimulate melanin synthesis in OCA2-deficient cells when localized to melanosomes but not when specifically retained in the ER, contradicting a proposed primary function for OCA2 in the ER. Steady-state melanosomal localization requires a conserved consensus acidic dileucine-based sorting motif within the cytoplasmic N-terminal region of OCA2. A second dileucine signal within this region confers steadystate lysosomal localization in melanocytes, suggesting that OCA2 might traverse multiple sequential or parallel trafficking routes. The two dileucine signals physically interact in a differential manner with cytoplasmic adaptors known to function in trafficking other proteins to melanosomes. We conclude that OCA2 is targeted to and functions within melanosomes but that residence within melanosomes may be regulated by secondary or alternative targeting to lysosomes. INTRODUCTIONMelanin pigments are synthesized by specialized cell types, including dermal and epidermal melanocytes and retinal pigment epithelial cells, within unique organelles known as melanosomes . Melanosomes are members of a class of tissue-specific "lysosome-related organelles" characterized by an acidic lumenal pH and the presence of some lysosomal proteins (Dell'Angelica et al., 2000;Griffiths, 2002). Among lysosome-related organelles, melanosomes represent a subclass that coexists with bona fide lysosomes in their host cells . Melanosomes are distinguished from lysosomes by the presence of cell-type-specific cargo proteins that confer unique functional and morphological properties. How these cargo proteins are diverted from traditional lysosomes and delivered to and maintained within melanosomes is incompletely understood, and the degree of cargo cross-talk between melanosomes and lysosomes is not known.Melanosomes undergo a program of maturation within melanocytes by the ordered delivery of cargoes to nascent melanosomes via specialized trafficking pathways . Some components of the melanosomal trafficking machinery are known, largely from analyses of the sorting of well-characterized cargo proteins, such as the melanogenic enzyme tyrosinase (Tyr) and tyrosinase-related protein 1 (Tyrp1), in both wild-type melanocytes and melanocytes derived from patients or mouse models of genetic hypopigmentary diseases such as Hermansky-Pudlak Syndrome (HPS) (Di Pietro and Dell'Angelica, 2005;Wei, 2006). Tyr and Tyrp1 contain cytoplasmic a...

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Molecular Regulation of Melanin Formation: Melanosome Transporter Proteins

Brilliant¹

2006

The Pigmentary System

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Melanosomal Defects in Melanocytes from Mice Lacking Expression of thePink-Eyed DilutionGene: Correction by Culture in the Presence of Excess Tyrosine

Cited by 56 publications

References 35 publications

Pink-eyed Dilution Protein Controls the Processing of Tyrosinase

Pink-eyed Dilution Protein Controls the Processing of Tyrosinase

Localization to Mature Melanosomes by Virtue of Cytoplasmic Dileucine Motifs Is Required for Human OCA2 Function

Molecular Regulation of Melanin Formation: Melanosome Transporter Proteins

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