Document Detail

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.
MedLine Citation:
PMID:  22496449     Owner:  NLM     Status:  MEDLINE    
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.
Marie-Jeanne Pierrat; Véronique Marsaud; Alain Mauviel; Delphine Javelaud
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2012-04-11
Journal Detail:
Title:  The Journal of biological chemistry     Volume:  287     ISSN:  1083-351X     ISO Abbreviation:  J. Biol. Chem.     Publication Date:  2012 May 
Date Detail:
Created Date:  2012-05-28     Completed Date:  2012-08-15     Revised Date:  2013-06-26    
Medline Journal Info:
Nlm Unique ID:  2985121R     Medline TA:  J Biol Chem     Country:  United States    
Other Details:
Languages:  eng     Pagination:  17996-8004     Citation Subset:  IM    
Institut Curie, Centre de Recherche, INSERM U1021, CNRS UMR3347, and Université Paris XI, 91400 Orsay, France.
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MeSH Terms
Base Sequence
Cell Line, Tumor
Chromatin Immunoprecipitation
DNA Primers
DNA, Neoplasm / genetics
Disease Progression
Electrophoretic Mobility Shift Assay
Gene Expression Regulation
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*
Reg. No./Substance:
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

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