Abstract
Clear cell sarcoma (CCS) harbors a pathognomonic chromosomal translocation fusing the Ewing's sarcoma gene (EWS) to the CREB family transcription factor ATF1 and exhibits melanocytic features. We show that EWS-ATF1 occupies the MITF promoter, mimicking melanocyte-stimulating hormone (MSH) signaling to induce expression of MITF, the melanocytic master transcription factor and an amplified oncogene in melanoma. Knockdown/rescue studies revealed that MITF mediates the requirement of EWS-ATF1 for CCS survival in vitro and in vivo as well as for melanocytic differentiation. Moreover, MITF and TFE3 reciprocally rescue one another in lines derived from CCS or pediatric renal carcinoma. Seemingly unrelated tumors thus employ distinct strategies to oncogenically dysregulate the MiT family, collectively broadening the definition of MiT-associated human cancers.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Activating Transcription Factor 1 / genetics
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Activating Transcription Factor 1 / metabolism*
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Animals
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Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / metabolism
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Cell Differentiation
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Cell Line, Tumor
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Cell Proliferation
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DNA-Binding Proteins / biosynthesis
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DNA-Binding Proteins / genetics
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DNA-Binding Proteins / metabolism*
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High Mobility Group Proteins / biosynthesis
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Humans
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Melanocyte-Stimulating Hormones / physiology
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Melanocytes / metabolism
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Melanocytes / pathology
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Melanoma / metabolism
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Melanoma / pathology
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Mice
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Mice, Nude
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Microphthalmia-Associated Transcription Factor / genetics
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Microphthalmia-Associated Transcription Factor / metabolism*
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Neoplasm Transplantation
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Nuclear Proteins / genetics
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Nuclear Proteins / metabolism*
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Oncogene Proteins, Fusion / genetics
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Oncogene Proteins, Fusion / physiology*
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Promoter Regions, Genetic
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RNA-Binding Protein EWS / genetics*
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Regulatory Factor X Transcription Factors
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SOXE Transcription Factors
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Sarcoma, Clear Cell / metabolism*
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Sarcoma, Clear Cell / pathology
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Signal Transduction
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Transcription Factors / biosynthesis
Substances
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ATF1 protein, human
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Activating Transcription Factor 1
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Basic Helix-Loop-Helix Leucine Zipper Transcription Factors
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DNA-Binding Proteins
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High Mobility Group Proteins
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MITF protein, human
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Microphthalmia-Associated Transcription Factor
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Nuclear Proteins
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Oncogene Proteins, Fusion
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RNA-Binding Protein EWS
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Regulatory Factor X Transcription Factors
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SOX10 protein, human
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SOXE Transcription Factors
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Sox10 protein, mouse
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TFE3 protein, human
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Transcription Factors
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Melanocyte-Stimulating Hormones