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Submitted on December 8, 2004
Accepted on August 9, 2005
Department of Biochemistry and Molecular Biology & The Center for Genetics and Molecular Medicine, University of Louisville School of Medicine, Louisville, Kentucky 40292
* To whom correspondence should be addressed. E-mail: bjclark{at}louisville.edu.
Several factors have been identified in the transcriptional repression of the StAR gene promoter; yet, no associating co-repressor complexes have been characterized for the mouse promoter in MA-10 mouse Leydig tumor cells. We now report that Sp3, CAGA element binding proteins, and a co-repressor complex consisting of mSin3A, HDAC1, and HDAC2 associates with a transcriptional repressor region within the mouse StAR promoter. 5' promoter deletion analysis localized the negative regulatory region between -180bp to -150bp upstream of the transcription start site and mutations in both the CAGA and Sp binding elements were required to relieve the repression of basal StAR promoter activity. Protein-DNA binding analysis revealed Sp3 and specific CAGA element binding protein(s) associated with the repressor region. Co-immunoprecipitation analysis identified the presence of the mSin3A, HDAC1, and HDAC2 co-repressor complex in MA-10 cells. Furthermore, chromatin immunoprecipitation (ChIP) assays revealed Sp3, mSin3A, and HDAC1/2 association with the proximal region of the StAR promoter in situ. In addition, HDAC inhibition resulted in a dose-dependent activation of a mouse StAR reporter construct, while mutations within the repressor region diminished this effect by 44%. In sum, these data support a novel regulatory mechanism for transcriptional repression of the mouse StAR promoter by DNA binding of Sp3 and CAGA element binding proteins, and association of the Sin3 co-repressor complex exhibiting histone deacetylase activity.
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