| Expression of microphthalmia-associated transcription factor (MITF), which is critical for melanoma progression, is inhibited by both transcription factor GLI2 and transforming growth factor-β. | |
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MedLine Citation:
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PMID: 22496449 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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The melanocyte-specific transcription factor M-MITF is involved in numerous aspects of melanoblast lineage biology including pigmentation, survival, and migration. It plays complex roles at all stages of melanoma progression and metastasis. We established previously that GLI2, a Kruppel-like transcription factor that acts downstream of Hedgehog signaling, is a direct transcriptional target of the TGF-β/SMAD pathway and contributes to melanoma progression, exerting antagonistic activities against M-MITF to control melanoma cell invasiveness. Herein, we dissected the molecular mechanisms underlying both TGF-β and GLI2-driven M-MITF gene repression. Using transient cell transfection experiments with M-MITF promoter constructs, chromatin immunoprecipitation, site-directed mutagenesis, and electrophoretic mobility shift assays, we identified a GLI2 binding site within the -334/-296 region of the M-MITF promoter, critical for GLI2-driven transcriptional repression. This region is, however, not needed for inhibition of M-MITF promoter activity by TGF-β. We determined that TGF-β rapidly repressed protein kinase A activity, thus reducing both phospho-cAMP-response element-binding protein (CREB) levels and CREB-dependent transcription of the M-MITF promoter. Increased GLI2 binding to its cognate cis-element, associated with reduced CREB-dependent transcription, allowed maximal inhibition of the M-MITF promoter via two distinct mechanisms. |
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Authors:
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Marie-Jeanne Pierrat; Véronique Marsaud; Alain Mauviel; Delphine Javelaud |
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Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't Date: 2012-04-11 |
Journal Detail:
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Title: The Journal of biological chemistry Volume: 287 ISSN: 1083-351X ISO Abbreviation: J. Biol. Chem. Publication Date: 2012 May |
Date Detail:
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Created Date: 2012-05-28 Completed Date: 2012-08-15 Revised Date: 2013-04-16 |
Medline Journal Info:
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Nlm Unique ID: 2985121R Medline TA: J Biol Chem Country: United States |
Other Details:
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Languages: eng Pagination: 17996-8004 Citation Subset: IM |
Affiliation:
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Institut Curie, Centre de Recherche, INSERM U1021, CNRS UMR3347, and Université Paris XI, 91400 Orsay, France. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Base Sequence Cell Line, Tumor Chromatin Immunoprecipitation DNA Primers DNA, Neoplasm / genetics Disease Progression Electrophoretic Mobility Shift Assay Gene Expression Regulation Humans Kruppel-Like Transcription Factors / physiology* Melanoma / pathology* Microphthalmia-Associated Transcription Factor / genetics*, physiology Molecular Sequence Data Nuclear Proteins / physiology* Promoter Regions, Genetic Regulatory Sequences, Nucleic Acid Transcription, Genetic Transforming Growth Factor beta / physiology* |
| Chemical | |
Reg. No./Substance:
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0/DNA Primers; 0/DNA, Neoplasm; 0/GLI2 protein, human; 0/Kruppel-Like Transcription Factors; 0/MITF protein, human; 0/Microphthalmia-Associated Transcription Factor; 0/Nuclear Proteins; 0/Transforming Growth Factor beta |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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