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David E Fisher - One of the best experts on this subject based on the ideXlab platform.
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mitf and uv responses in skin from pigmentation to addiction
Pigment Cell & Melanoma Research, 2019Co-Authors: Nhu T Nguyen, David E FisherAbstract:Ultraviolet radiation (UVR) has numerous effects on skin, including DNA damage, tanning, vitamin D synthesis, carcinogenesis, and immunomodulation. Keratinocytes containing damaged DNA secrete both α-melanocyte-stimulating hormone (α-MSH), which stimulates pigment production by melanocytes, and the opioid β-endorphin, which can trigger addiction-like responses to UVR. The pigmentation (tanning) response is an adaptation that provides some delayed protection against further DNA damage and carcinogenesis, while the opioid response may be an evolutionary adaptation for promoting sun-seeking behavior to prevent vitamin D deficiency. Here, we review the pigmentation response to UVR, driven by melanocytic Microphthalmia-Associated Transcription Factor (MITF), and evidence for UVR-induced melanomagenesis and addiction. We also discuss potential applications of a novel approach to generate protective pigmentation in the absence of UVR (sunless tanning) using a topical small-molecule inhibitor of the salt-inducible kinase (SIK) family.
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The master role of Microphthalmia-Associated Transcription Factor in melanocyte and melanoma biology
Laboratory Investigation, 2017Co-Authors: Akinori Kawakami, David E FisherAbstract:Certain Transcription Factors have vital roles in lineage development, including specification of cell types and control of differentiation. Microphthalmia-Associated Transcription Factor (MITF) is a key Transcription Factor for melanocyte development and differentiation. MITF regulates expression of numerous pigmentation genes to promote melanocyte differentiation, as well as fundamental genes for maintaining cell homeostasis, including genes encoding proteins involved in apoptosis (eg, BCL2 ) and the cell cycle (eg, CDK2 ). Loss-of-function mutations of MITF cause Waardenburg syndrome type IIA, whose phenotypes include depigmentation due to melanocyte loss, whereas amplification or specific mutation of MITF can be an oncogenic event that is seen in a subset of familial or sporadic melanomas. In this article, we review basic features of MITF biological function and highlight key unresolved questions regarding this remarkable Transcription Factor.
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the roles of microphthalmia associated Transcription Factor and pigmentation in melanoma
Archives of Biochemistry and Biophysics, 2014Co-Authors: Jennifer Jiaan Hsiao, David E FisherAbstract:MITF and pigmentation play important roles in both normal melanocyte and transformed melanoma cell biology. MITF is regulated by many pathways and it also regulates many targets, some of which are still being discovered and functionally validated. MITF is involved in a wide range of processes in melanocytes, including pigment synthesis and lineage survival. Pigmentation itself plays an important role as the interface between genetic and environmental Factors that contribute to melanoma.
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regulation of mitf stability by the usp13 deubiquitinase
Nature Communications, 2011Co-Authors: Xiansi Zhao, Akinori Kawakami, Brian P Fiske, David E FisherAbstract:The Microphthalmia-Associated Transcription Factor (MITF) is essential for melanocyte development. Mutation-induced MAPK pathway activation is common in melanoma and induces MITF phosphorylation, ubiquitination, and proteolysis. Little is known about the enzymes involved in MITF ubiquitination/deubiquitination. Here we report the identification of a deubiquitinating enzyme, named ubiquitin-specific protease 13 (USP13) that appears to be responsible for MITF deubiquitination, utilizing a short hairpin RNA library against known deubiquitinating enzymes. Through deubiquitination, USP13 stabilizes and upregulates MITF protein levels. Conversely, suppression of USP13 (through knockdown) leads to dramatic loss of MITF protein, but not messenger RNA. Through its effects on MITF deubiquitination, USP13 was observed to modulate expression of MITF downstream target genes and, thereby, to be essential for melanoma growth in soft agar and in nude mice. These observations suggest that as a potentially drugable protease, USP13 might be a viable therapeutic target for melanoma.
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sphingosine 1 phosphate decreases melanin synthesis via microphthalmia associated Transcription Factor phosphorylation through the s1p3 receptor subtype
Journal of Pharmacy and Pharmacology, 2011Co-Authors: Dong-seok Kim, David E Fisher, Arlo J Miller, Seohyoung Park, Yunmi Jeong, Sunbang Kwon, Kyoungchan ParkAbstract:Objectives Previously, we reported that sphingosine-1-phosphate (S1P) reduced melanin synthesis. In this study we have investigated S1P receptor-mediated extracellular signal-regulated protein kinase (ERK) activation and Microphthalmia-Associated Transcription Factor (MITF) phosphorylation. Methods To examine S1P-induced signalling pathways, electron and confocal microscopic studies, reverse Transcription-polymerase chain reaction and Western blot analysis were performed. Key findings S1P phosphorylated MITF at Ser73, which may have resulted in a MITF mobility shift. Furthermore, 90 kDa ribosomal S6 kinase-1 (RSK-1) phosphorylation was observed after S1P treatment. In addition, PD98059 abrogated the S1P-induced MITF mobility shift and RSK-1 activation. In experiments with MITF mutants, it was shown that dual phosphorylation at Ser73 and Ser409 was indispensable for MITF degradation. We investigated further the actions of S1P on its specific receptors. The results showed that pertussis toxin completely abolished the hypopigmentary effects and ERK pathway activation by S1P, suggesting that S1P regulated melanogenesis via its receptor. The use of specific receptor antagonists indicated that the S1P3 receptor was dominantly involved in S1P-induced ERK activation and hypopigmentation. Conclusions The results suggested that S1P reduced melanin synthesis via S1P3 receptor-mediated ERK and RSK-1 activation, and subsequent MITF dual phosphorylation and degradation.
I L De La Serna - One of the best experts on this subject based on the ideXlab platform.
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baf60a mediates interactions between the microphthalmia associated Transcription Factor and the brg1 containing swi snf complex during melanocyte differentiation
Journal of Cellular Physiology, 2019Co-Authors: Srinivas Vinod Saladi, Shweta Aras, Tupa Basuroy, Himangi Marathe, Patrick Lores, I L De La SernaAbstract:SWI/SNF chromatin remodeling enzymes are multisubunit complexes that contain one of two catalytic subunits, BRG1 or BRM and 9-11 additional subunits called BRG1 or BRM-associated Factors (BAFs). BRG1 interacts with the Microphthalmia-Associated Transcription Factor (MITF) and is required for melanocyte development in vitro and in vivo. The subunits of SWI/SNF that mediate interactions between BRG1 and MITF have not been elucidated. Three mutually exclusive isoforms of a 60-kDa subunit (BAF60A, B, or C) often facilitate interactions with Transcription Factors during lineage specification. We tested the hypothesis that a BAF60 subunit promotes interactions between MITF and the BRG1-containing SWI/SNF complex. We found that MITF can physically interact with BAF60A, BAF60B, and BAF60C. The interaction between MITF and BAF60A required the basic helix-loop-helix domain of MITF. Recombinant BAF60A pulled down recombinant MITF, suggesting that the interaction can occur in the absence of other SWI/SNF subunits and other Transcriptional regulators of the melanocyte lineage. Depletion of BAF60A in differentiating melanoblasts inhibited melanin synthesis and expression of MITF target genes. MITF promoted BAF60A recruitment to melanocyte-specific promoters, and BAF60A was required to promote BRG1 recruitment and chromatin remodeling. Thus, BAF60A promotes interactions between MITF and the SWI/SNF complex and is required for melanocyte differentiation.
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heterogeneous swi snf chromatin remodeling complexes promote expression of microphthalmia associated Transcription Factor target genes in melanoma
Oncogene, 2010Co-Authors: Bridget Keenen, Srinivas Vinod Saladi, Miranda Yeung, I L De La SernaAbstract:The Microphthalmia-Associated Transcription Factor (MITF) promotes melanocyte differentiation and cell cycle arrest. Paradoxically, MITF also promotes melanoma survival and proliferation, acting like a lineage survival oncogene. Thus, it is critically important to understand the mechanisms that regulate MITF activity in melanoma cells. SWI/SNF chromatin remodeling enzymes are multiprotein complexes composed of one of two related ATPases, BRG1 or BRM, and 9-12 associated Factors (BAFs). We previously determined that BRG1 interacts with MITF to promote melanocyte differentiation. However, it was unclear whether SWI/SNF enzymes regulate the expression of different classes of MITF target genes in melanoma. In this study, we characterized SWI/SNF subunit expression in melanoma cells and observed down-regulation of BRG1 or BRM, but not concomitant loss of both ATPases. Re-introduction of BRG1 in BRG1 deficient SK-MEL5 cells enhanced expression of differentiation specific MITF target genes and resistance to cisplatin. Down-regulation of the single ATPase, BRM, in SK-MEL5 cells inhibited expression of both differentiation specific and pro-proliferative MITF target genes and inhibited tumorigenicity in vitro. Our data suggest that heterogeneous SWI/SNF complexes composed of either the BRG1 or BRM subunit promote expression of distinct and overlapping MITF target genes and that at least one ATPase is required for melanoma tumorigenicity.
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the microphthalmia associated Transcription Factor requires swi snf enzymes to activate melanocyte specific genes
Journal of Biological Chemistry, 2006Co-Authors: I L De La Serna, Yasuyuki Ohkawa, Chiduru Higashi, Chaitali Dutta, Jules Osias, Naveen Kommajosyula, Taro Tachibana, Anthony N ImbalzanoAbstract:The microphthalmia Transcription Factor (Mitf) activates melanocyte-specific gene expression, is critical for survival and proliferation of melanocytes during development, and has been described as an oncogene in malignant melanoma. SWI/SNF complexes are ATP-dependent chromatin-remodeling enzymes that play a role in many developmental processes. To determine the requirement for SWI/SNF enzymes in melanocyte differentiation, we introduced Mitf into fibroblasts that inducibly express dominant negative versions of the SWI/SNF ATPases, Brahma or Brahma-related gene 1 (BRG1). These dominant negative SWI/SNF components have been shown to inhibit gene activation events that normally require SWI/SNF enzymes. We found that Mitf-mediated activation of a subset of endogenous melanocyte-specific genes required SWI/SNF enzymes but that cell-cycle regulation occurred independently of SWI/SNF function. Activation of tyrosinase-related protein 1, a melanocyte-specific gene, correlated with SWI/SNF-dependent changes in chromatin accessibility at the endogenous locus. Both BRG1 and Mitf could be localized to the tyrosinase-related protein 1 and tyrosinase promoters by chromatin immunoprecipitation, whereas immunofluorescence and immunoprecipitation experiments indicate that Mitf and BRG1 co-localized in the nucleus and physically interacted. Together these results suggest that Mitf can recruit SWI/SNF enzymes to melanocyte-specific promoters for the activation of gene expression via induced changes in chromatin structure at endogenous loci.
Nancy J Philp - One of the best experts on this subject based on the ideXlab platform.
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microphthalmia associated Transcription Factor mitf promotes differentiation of human retinal pigment epithelium rpe by regulating micrornas 204 211 expression
Journal of Biological Chemistry, 2012Co-Authors: Jeffrey Adijanto, John J Castorino, Zixuan Wang, Arvydas Maminishkis, Gerald B Grunwald, Nancy J PhilpAbstract:The retinal pigment epithelium (RPE) plays a fundamental role in maintaining visual function and dedifferentiation of RPE contributes to the pathophysiology of several ocular diseases. To identify microRNAs (miRNAs) that may be involved in RPE differentiation, we compared the miRNA expression profiles of differentiated primary human fetal RPE (hfRPE) cells to dedifferentiated hfRPE cells. We found that miR-204/211, the two most highly expressed miRNAs in the RPE, were significantly down-regulated in dedifferentiated hfRPE cells. Importantly, transfection of pre-miR-204/211 into hfRPE cells promoted differentiation whereas adding miR-204/211 inhibitors led to their dedifferentiation. Microphthalmia-Associated Transcription Factor (MITF) is a key regulator of RPE differentiation that was also down-regulated in dedifferentiated hfRPE cells. MITF knockdown decreased miR-204/211 expression and caused hfRPE dedifferentiation. Significantly, co-transfection of MITF siRNA with pre-miR-204/211 rescued RPE phenotype. Collectively, our data show that miR-204/211 promote RPE differentiation, suggesting that miR-204/211-based therapeutics may be effective treatments for diseases that involve RPE dedifferentiation such as proliferative vitreoretinopathy.
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microphthalmia associated Transcription Factor mitf promotes differentiation of human retinal pigment epithelium rpe by regulating micrornas 204 211 expression
Journal of Biological Chemistry, 2012Co-Authors: Jeffrey Adijanto, John J Castorino, Zixuan Wang, Arvydas Maminishkis, Gerald B Grunwald, Nancy J PhilpAbstract:Abstract The retinal pigment epithelium (RPE) plays a fundamental role in maintaining visual function and dedifferentiation of RPE contributes to the pathophysiology of several ocular diseases. To identify microRNAs (miRNAs) that may be involved in RPE differentiation, we compared the miRNA expression profiles of differentiated primary human fetal RPE (hfRPE) cells to dedifferentiated hfRPE cells. We found that miR-204/211, the two most highly expressed miRNAs in the RPE, were significantly down-regulated in dedifferentiated hfRPE cells. Importantly, transfection of pre-miR-204/211 into hfRPE cells promoted differentiation whereas adding miR-204/211 inhibitors led to their dedifferentiation. Microphthalmia-Associated Transcription Factor (MITF) is a key regulator of RPE differentiation that was also down-regulated in dedifferentiated hfRPE cells. MITF knockdown decreased miR-204/211 expression and caused hfRPE dedifferentiation. Significantly, co-transfection of MITF siRNA with pre-miR-204/211 rescued RPE phenotype. Collectively, our data show that miR-204/211 promote RPE differentiation, suggesting that miR-204/211-based therapeutics may be effective treatments for diseases that involve RPE dedifferentiation such as proliferative vitreoretinopathy.
Shigeki Shibahara - One of the best experts on this subject based on the ideXlab platform.
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induction of mitf expression in human cholangiocarcinoma cells and hepatocellular carcinoma cells by cyclopamine an inhibitor of the hedgehog signaling
Biochemical and Biophysical Research Communications, 2016Co-Authors: Papavee Samatiwat, Kazuhisa Takeda, Soisungwan Satarug, Koji Ohba, Veerapol Kukongviriyapan, Shigeki ShibaharaAbstract:Microphthalmia-Associated Transcription Factor (MITF) is a key regulator of differentiation of melanocytes and retinal pigment epithelial cells, but it also has functions in non-pigment cells. MITF consists of multiple isoforms, including widely expressed MITF-A and MITF-H. In the present study, we explored the potential role played by the Hedgehog signaling on MITF expression in two common types of primary liver cancer, using human cholangiocarcinoma cell lines, the KKU-100 and HuCCT1, along with the HepG2 human hepatocellular carcinoma cell line. Importantly, cholangiocarcinoma is characterized by the activated Hedgehog signaling. Here we show that MITF-A mRNA is predominantly expressed in all three human liver cancer cell lines examined. Moreover, cyclopamine, an inhibitor of the Hedgehog signalling, increased the expression levels of MITF proteins in HuCCT1 and HepG2 cells, but not in KKU-100 cells, suggesting that MITF expression may be down-regulated in some liver cancer cases.
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microphthalmia associated Transcription Factor interacts with lef 1 a mediator of wnt signaling
The EMBO Journal, 2002Co-Authors: Kenichi Yasumoto, Kazuhiro Takahashi, Kazuhisa Takeda, Kenichi Watanabe, Hideo Saito, Shigeki ShibaharaAbstract:Wnt signals regulate differentiation of neural crest cells through the β-catenin associated with a nuclear mediator of the lymphoid-enhancing Factor 1 (LEF-1)/T-cell Factors (TCFs) family. Here we show the interaction between the basic helix–loop–helix and leucine-zipper region of Microphthalmia-Associated Transcription Factor (MITF) and LEF-1. MITF is essential for melanocyte differentiation and its heterozygous mutations cause auditory–pigmentary syndromes. Functional cooperation of MITF with LEF-1 results in synergistic transactivation of the dopachrome tautomerase (DCT) gene promoter, an early melanoblast marker. This activation depends on the separate cis-acting elements, which are also responsible for the induction of the DCT promoter by lithium chloride that mimics Wnt signaling. β-catenin is required for efficient transactivation, but dispensable for the interaction between MITF and LEF-1. The interaction with MITF is unique to LEF-1 and not detectable with TCF-1. LEF-1 also cooperates with the MITF-related proteins, such as TFE3, to transactivate the DCT promoter. This study therefore suggests that the MITF/TFE3 family is a new class of nuclear modulators for LEF-1, which may ensure efficient propagation of Wnt signals in many types of cells.
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induction of melanocyte specific microphthalmia associated Transcription Factor by wnt 3a
Journal of Biological Chemistry, 2000Co-Authors: Kazuhisa Takeda, Kenichi Yasumoto, Kazuhiro Takahashi, Ritsuko Takada, Shinji Takada, Kenichi Watanabe, Tetsuo Udono, Hideo Saito, Shigeki ShibaharaAbstract:Microphthalmia-Associated Transcription Factor (Mitf) plays a critical role in the development of neural crest-derived melanocytes. Here, we show that exogenously added Wnt-3a protein, an intercellular signaling molecule, up-regulates the expression of endogenous melanocyte-specific Mitf (Mitf-M) mRNA in cultured melanocytes. The melanocyte-specific promoter of the human MITF gene (MITF-M promoter) contains a functional LEF-1-binding site, which is bound in vitro by LEF-1 and confers the preferential expression on a reporter gene in melanocytes and melanoma cells, as judged by the transient transfection assays. Moreover, the LEF-1-binding site is required for the transactivation of a reporter gene by LEF-1, beta-catenin, or their combination. Exogenously added Wnt-3a protein also transactivates the MITF-M promoter via the LEF-1-binding site; this activation was abolished when a dominant-negative form of LEF-1 was coexpressed. These results suggest that Wnt-3a signaling recruits beta-catenin and LEF-1 to the LEF-1-binding site of the MITF-M promoter. Therefore, the present study identifies Mitf-M/MITF-M as a direct target of Wnt signaling.
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functional analysis of microphthalmia associated Transcription Factor in pigment cell specific Transcription of the human tyrosinase family genes
Journal of Biological Chemistry, 1997Co-Authors: Kenichi Yasumoto, Yasushi Tomita, Kouji Yokoyama, Kazuhiro Takahashi, Shigeki ShibaharaAbstract:Tyrosinase, tyrosinase-related protein-1 (TRP-1), and TRP-2 are the enzymes involved in melanin biosynthesis and are preferentially expressed in pigment cells. Their human gene promoters share the 11-base pair M box containing a CATGTG motif, which was shown here to be bound in vitro by Microphthalmia-Associated Transcription Factor (MITF). Transient cotransfection analysis showed that MITF overexpression increased the expression of a reporter gene under the control of the human tyrosinase or TRP-1 gene promoter but not the TRP-2 promoter. The promoter activation caused by MITF is dependent on each CATGTG motif of the distal enhancer element, the M box, and the initiator E box of the tyrosinase gene and the TRP-1 M box. Furthermore, a truncated MITF lacking the carboxyl-terminal 125 amino acid residues transactivated the tyrosinase promoter less efficiently than did MITF, suggesting that MITF's carboxyl terminus contains a Transcriptional activation domain, but unexpectedly such a truncated MITF remarkably transactivated the TRP-2 gene promoter. These results suggest that MITF is sufficient to direct pigment cell-specific Transcription of the tyrosinase and TRP-1 genes but not the TRP-2 gene.
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microphthalmia associated Transcription Factor as a regulator for melanocyte specific Transcription of the human tyrosinase gene
Molecular and Cellular Biology, 1994Co-Authors: Kenichi Yasumoto, Yasushi Tomita, Kouji Yokoyama, Koushi Shibata, Shigeki ShibaharaAbstract:Tyrosinase is a rate-limiting enzyme in melanin biosynthesis and is specifically expressed in differentiated melanocytes. We have identified the enhancer element in the 5'-flanking region of the human tyrosinase gene that is responsible for its pigment cell-specific Transcription and have termed it tyrosinase distal element (TDE) (positions -1861 to -1842). Transient expression assays showed that TDE confers efficient expression of a firefly luciferase reporter gene linked to the tyrosinase gene promoter in MeWo pigmented melanoma cells but not in HeLa cells, which do not express tyrosinase. TDE was specifically bound by nuclear proteins of MeWo and HeLa cells, the binding properties of which were indistinguishable in gel mobility shift assays. TDE contains the CATGTG motif in its center, and mutation analysis indicates that the CA dinucleotides of this motif are crucial for protein binding and pigment cell-specific enhancer function. The CATGTG motif is consistent with the consensus sequence recognized by a large family of Transcription Factors with a basic helix-loop-helix structure, which prompted us to examine the possible involvement of a ubiquitous Transcription Factor, USF, and a novel Factor, Microphthalmia-Associated Transcription Factor (MITF), recently cloned as the human homolog of the mouse microphthalmia (mi) gene product. The mi phenotype is associated with a mutant mi locus and characterized by small eyes and loss of melanin pigments. Both USF and MITF are predicted to contain a basic helix-loop-helix structure and a leucine zipper structure. We provide evidence that USF binds to TDE, whereas we were unable to detect the DNA-binding activity of MITF. Transient coexpression assays showed that MITF specifically transactivates the promoter activity of the tyrosinase gene through the CATGTG motif of TDE but not the promoter of the ubiquitously expressed heme oxygenase gene, while USF is able to activate both promoters. These results indicate that MITF is a cell-type-specific Factor that is capable of activating Transcription of the tyrosinase gene.
Hans R Widlund - One of the best experts on this subject based on the ideXlab platform.
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a novel role for microphthalmia associated Transcription Factor regulated pigment epithelium derived Factor during melanoma progression
American Journal of Pathology, 2015Co-Authors: Soheil S Dadras, Akinori Kawakami, Richard J Lin, Gita Razavi, Erez Feige, Danny A Milner, Massimo Loda, Scott R Granter, Michael Detmar, Hans R WidlundAbstract:Microphthalmia-Associated Transcription Factor (MITF) acts via pigment epithelium-derived Factor (PEDF), an antiangiogenic protein, to regulate retinal pigment epithelium migration. PEDF expression and/or regulation during melanoma development have not been investigated previously. Using immunohistochemistry, we determined expression of PEDF in common and dysplastic melanocytic nevi, melanoma in situ , invasive melanoma, and metastatic melanoma ( n = 102). PEDF expression was consistently decreased in invasive and metastatic melanoma, compared with nevi and melanoma in situ ( P P = 0.003), and correlated with depth of invasion ( P = 0.003) and distant metastasis ( P = 0.0331), but only marginally with mitotic index, AJCC stage, nodal metastasis, or blood vascular density (0.05 P P = 0.0003). Searching for PEDF regulatory mechanisms revealed two occupied conserved E-boxes (DNA recognition elements) in the first intron of the human and mouse PEDF promoter regions, confirmed by binding assays. Dominant-negative and siRNA approaches in vivo demonstrated direct Transcriptional influence of MITF on PEDF, establishing the PEDF gene ( SERPINF1 ) as a MITF target in melanocytes and melanoma cells. These findings suggest that loss of PEDF expression promotes early invasive melanoma growth.
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pharmacologic suppression of mitf expression via hdac inhibitors in the melanocyte lineage
Pigment Cell & Melanoma Research, 2008Co-Authors: Satoru Yokoyama, Mehdi Khaled, Hans R Widlund, Carmit Levy, Erez Feige, Laura L Poling, Andrew L Kung, David E FisherAbstract:Melanoma incidence continues to rise at an alarming rate while effective systemic therapies remain very limited. Microphthalmia-Associated Transcription Factor (MITF) is required for development of melanocytes and is an amplified oncogene in a fraction of human melanomas. Microphthalmia-Associated Transcription Factor also plays an oncogenic role in human clear cell sarcomas, which typically exhibit melanoma-like features. Although pharmacologic suppression of MITF is of potential interest in a variety of clinical settings, it is not known to contain intrinsic catalytic activity capable of direct small molecule inhibition. An alternative drug-targeting strategy is to identify and interfere with lineage-restricted mechanisms required for its expression. Here, we report that multiple histone deacetylase (HDAC)-inhibitor drugs potently suppress MITF expression in melanocytes, melanoma and clear cell sarcoma cells. Although HDAC inhibitors may affect numerous cellular targets, we observed suppression of skin pigmentation by topical drug application as well as evidence of anti-melanoma efficacy in vitro and in mouse xenografts. Consequently, HDAC inhibitor drugs are candidates to play therapeutic roles in targeting conditions affecting the melanocyte lineage.
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a tissue restricted camp Transcriptional response sox10 modulates α melanocyte stimulating hormone triggered expression of microphthalmia associated Transcription Factor in melanocytes
Journal of Biological Chemistry, 2003Co-Authors: Wade E Huber, Roydon E Price, Hans R Widlund, Ian J Davis, Michael Wegner, David E FisherAbstract:alpha-Melanocyte-stimulating hormone (MSH) utilizes cAMP to trigger pigmentation of melanocytes via activation of melanocyte-restricted Microphthalmia-Associated Transcription Factor (M-MITF) expression. M-MITF is a melanocyte-restricted helix-loop-helix Transcription Factor capable of transactivating promoters for multiple genes whose products modulate pigmentation. Although M-MITF promoter activation by MSH is known to occur through a conserved cAMP-response element (CRE), it remains unclear how this CRE exhibits such exquisitely tissue-restricted responsiveness. Here we show that cAMP-mediated CRE-binding protein activation of the M-MITF promoter requires a second DNA element located approximately 100 bp upstream, a site that is bound and activated by SOX10. Mutations in the SOX10 Transcription Factor, like MITF, results in a disorder known as Waardenburg Syndrome. The cAMP response of the M-MITF promoter was analyzed in melanoma and neuroblastoma cells (which are neural crest-derived but lack both M-MITF and SOX10 expression). M-MITF promoter responsiveness to cAMP was found to depend upon SOX10, and reciprocally, SOX10 transactivation was dependent upon the CRE. Ectopic SOX10 expression, in cooperation with cAMP signaling, activated the M-MITF promoter function and the expression of measurable endogenous M-MITF transcripts in neuroblastoma cells. SOX10dom, a mutant allele, failed to cooperate with cAMP in neuroblastoma cells and attenuated the cAMP responsiveness of the M-MITF promoter in melanoma cells. These observations demonstrate a means whereby the ubiquitous cAMP signaling machinery is harnessed to produce a highly tissue-restricted Transcriptional response by cooperating with architectural Factors, in this case SOX10.
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a tissue restricted camp Transcriptional response sox10 modulates α melanocyte stimulating hormone triggered expression of microphthalmia associated Transcription Factor in melanocytes
Journal of Biological Chemistry, 2003Co-Authors: Wade E Huber, Roydon E Price, Hans R Widlund, Ian J Davis, Michael Wegner, David E FisherAbstract:α-Melanocyte-stimulating hormone (MSH) utilizes cAMP to trigger pigmentation of melanocytes via activation of melanocyte-restricted Microphthalmia-Associated Transcription Factor (M-MITF) expression. M-MITF is a melanocyte-restricted helix-loop-helix Transcription Factor capable of transactivating promoters for multiple genes whose products modulate pigmentation. Although M-MITF promoter activation by MSH is known to occur through a conserved cAMP-response element (CRE), it remains unclear how this CRE exhibits such exquisitely tissue-restricted responsiveness. Here we show that cAMP-mediated CRE-binding protein activation of the M-MITF promoter requires a second DNA element located ∼100 bp upstream, a site that is bound and activated by SOX10. Mutations in the SOX10 Transcription Factor, like MITF, results in a disorder known as Waardenburg Syndrome. The cAMP response of the M-MITF promoter was analyzed in melanoma and neuroblastoma cells (which are neural crest-derived but lack both M-MITF and SOX10 expression). M-MITF promoter responsiveness to cAMP was found to depend upon SOX10, and reciprocally, SOX10 transactivation was dependent upon the CRE. Ectopic SOX10 expression, in cooperation with cAMP signaling, activated the M-MITF promoter function and the expression of measurable endogenous M-MITF transcripts in neuroblastoma cells. SOX10dom, a mutant allele, failed to cooperate with cAMP in neuroblastoma cells and attenuated the cAMP responsiveness of the M-MITF promoter in melanoma cells. These observations demonstrate a means whereby the ubiquitous cAMP signaling machinery is harnessed to produce a highly tissue-restricted Transcriptional response by cooperating with architectural Factors, in this case SOX10.
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β catenin induced melanoma growth requires the downstream target microphthalmia associated Transcription Factor
Journal of Cell Biology, 2002Co-Authors: Hans R Widlund, Roydon E Price, Martin A Horstmann, Junqing Cui, Stephen L Lessnick, David E FisherAbstract:The Transcription Factor Microphthalmia-Associated Transcription Factor (MITF) is a lineage-determination Factor, which modulates melanocyte differentiation and pigmentation. MITF was recently shown to reside downstream of the canonical Wnt pathway during melanocyte differentiation from pluripotent neural crest cells in zebrafish as well as in mammalian melanocyte lineage cells. Although expression of many melanocytic/pigmentation markers is lost in human melanoma, MITF expression remains intact, even in unpigmented tumors, suggesting a role for MITF beyond its role in differentiation. A significant fraction of primary human melanomas exhibit deregulation (via aberrant nuclear accumulation) of beta-catenin, leading us to examine its role in melanoma growth and survival. Here, we show that beta-catenin is a potent mediator of growth for melanoma cells in a manner dependent on its downstream target MITF. Moreover, suppression of melanoma clonogenic growth by disruption of beta-catenin-T-cell Transcription Factor/LEF is rescued by constitutive MITF. This rescue occurs largely through a prosurvival mechanism. Thus, beta-catenin regulation of MITF expression represents a tissue-restricted pathway that significantly influences the growth and survival behavior of this notoriously treatment-resistant neoplasm.