Aberrant retention of tyrosinase in the endoplasmic reticulum mediates accelerated degradation of the enzyme and contributes to the dedifferentiated phenotype of amelanotic melanoma cells

Halaban, Ruth; Cheng, Elaine; Zhang, Yuhua; Moellmann, Gisela; Hanlon, Douglas; Michalak, Marek; Setaluri, Vijayasaradhi; Hebert, Daniel N.

doi:10.1073/pnas.94.12.6210

Cited by 247 publications

(272 citation statements)

References 49 publications

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“…The observation that exogenous Mitf-M fails to reactivate the tyrosinase promoter in melanoma cells that have lost expression of Mitf-M (Vachtenheim et al, 2001) suggests that Mitf-M might, likewise, not be able to activate the tyrosinase promoter in CCS cells. Alternatively, degradation of tyrosinase protein similar to that which occurs in amelanotic melanoma (Halaban et al, 1997) might explain lack of tyrosinase in cultured CCS cells. The above possibilities remain to be examined.…”

Section: Discussionmentioning

confidence: 99%

The melanocyte inducing factor MITF is stably expressed in cell lines from human clear cell sarcoma

Goodall

Goding

et al. 2003

Br J Cancer

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Clear cell sarcoma (CCS) is associated with the EWS/ATF1 oncogene that is created by chromosomal fusion of the Ewings Sarcoma oncogene (EWS) and the cellular transcription factor ATF1. The melanocytic character of CCS suggests that the microphthalmiaassociated transcription factor (Mitf), a major inducer of melanocytic differentiation, may be miss-expressed in CCS. Accordingly, we show that the mRNA and protein of the melanocyte-specific isoform of Mitf (Mitf-M) are present in several cultured CCS cell lines (Su-ccs-1, DTC1, Kao, MST-1, MST-2 and MST-3). The above cell lines thus provide a valuable experimental resource for examining the role of Mitf-M in both CCS and melanocyte differentiation. Melanocyte-specific expression of Mitf-M is achieved via an ATFdependent melanocyte-specific cAMP-response element in the Mitf-M promoter, and expression of Mitf-M in CCS cells suggests that EWS/ATF1 (a potent and promiscuous activator of cAMP-inducible promoters) may activate the Mitf-M promoter. Surprisingly, however, the Mitf-M promoter is not activated by EWS/ATF1 in transient assays employing CCS cells, melanocytes or nonmelanocytic cells. Thus, our results indicate that Mitf-M promoter activation may require an appropriate chromosomal context in CCS cells or alternatively that the Mitf-M promoter is not directly activated by EWS/ATF1.

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Section: Discussionmentioning

confidence: 99%

The melanocyte inducing factor MITF is stably expressed in cell lines from human clear cell sarcoma

Goodall

Goding

et al. 2003

Br J Cancer

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“…Tyrosinase can be inactivated in melanoma cells in response to acidified conditions, and the inactive tyrosinase accumulates in the endoplasmic reticulum (22). Importantly, restoration of tyrosinase activity in melanoma cells was demonstrated recently through restriction of glucose uptake (23), suggesting a direct link between glucose metabolism, tyrosinase expression and processing, and melanin synthesis.…”

Section: Discussionmentioning

confidence: 99%

Genes and pathways downstream of telomerase in melanoma metastasis

Bagheri

Nosrati

Li³

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

124

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Recent studies have demonstrated a role for telomerase in driving tumor progression, but its mechanism of action remains unclear. Here we show that stable, ribozyme-mediated suppression of mouse telomerase RNA reduced telomerase RNA expression, telomerase activity, and telomere length, which significantly reduced tumor invasion and metastatic potential. Our studies reveal that previously unidentified effects of telomerase may mediate its tumor-promoting effects. First, reducing telomerase activity induced a more dendritic morphology, accompanied by increased melanin content and increased expression of tyrosinase, a key enzyme in melanin biosynthesis. Second, gene expression profiling revealed that telomerase targeting down-regulated expression of several glycolytic pathway genes, with a corresponding decrease in glucose consumption and lactate production. Thus, telomerase activity controls the glycolytic pathway, potentially altering the energy state of tumor cells and thereby modulating tyrosinase activity and melanin production. These studies have important implications for understanding the mechanisms by which telomerase promotes tumor invasion and metastasis.differentiation ͉ glycolysis T elomerase is a ribonucleoprotein complex composed of core protein (telomerase reverse transcriptase) and RNA (telomerase RNA or TER) moieties. The most extensively characterized function of telomerase is to maintain the telomeric repeats capping the ends of eukaryotic chromosomes and thereby preserve their integrity by preventing end-to-end fusions (1-4). Whereas normal somatic cells have diminished telomerase activity, Ͼ90% of human cancers overexpress telomerase (5, 6). The well established roles for telomerase in tumor initiation and cellular immortalization (7,8) have led to the identification of telomerase as a potentially important molecular target in cancer therapeutics (9-11). To date, multiple studies have examined the utility of targeting telomerase to inhibit tumor cell proliferation (12-16).Although the importance of telomerase for tumor cell proliferation is well documented, its impact on tumor invasion and metastasis has been studied less. In our recent study, we used a systemic injection model of an effective anti-telomerase ribozyme to reveal that inhibiting telomerase activity in tumorbearing mice significantly reduces metastatic progression (16). Here, we examine the direct role played by telomerase in the metastatic potential of murine melanoma and characterize cellular pathways altered by telomerase suppression in tumor cells. We show that stable, ribozyme-mediated suppression of TER levels in melanoma cells results in a more dendritic phenotype, accompanied by increased tyrosinase expression and pigment production. Furthermore, we show that TER suppression results in down-regulation of glycolytic pathway genes and significantly reduces glucose metabolism, providing a mechanistic basis for the reduced metastatic capacity and increased pigment production observed. ResultsTo directly examine the role of te...

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“…Endoglycosidase H removes high-mannose glycans from glycoproteins in the ER. Complex glycan processing occurs in the medial-Golgi and renders proteins resistant to endoglycosidase H digestion (Halaban et al, 1997). Thus, this 66-kDa form represents an ER-retained Tyr.…”

Section: A Higher Percentage Of Tyr Is Retained In Er Of Melan-p1 Celmentioning

confidence: 99%

Pink-eyed Dilution Protein Controls the Processing of Tyrosinase

Chen

Manga

Orlow

2002

MBoC

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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Aberrant retention of tyrosinase in the endoplasmic reticulum mediates accelerated degradation of the enzyme and contributes to the dedifferentiated phenotype of amelanotic melanoma cells

Cited by 247 publications

References 49 publications

The melanocyte inducing factor MITF is stably expressed in cell lines from human clear cell sarcoma

The melanocyte inducing factor MITF is stably expressed in cell lines from human clear cell sarcoma

Genes and pathways downstream of telomerase in melanoma metastasis

Pink-eyed Dilution Protein Controls the Processing of Tyrosinase

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