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Submitted on August 3, 2005
Accepted on October 12, 2005
Departments of Microbiology, Urologyand Pharmacologyand the NYU Cancer Institute, NYU School of Medicine, 550 First Avenue, New York, N.Y. 10016, Hospital for Special Surgery, Cornell University School of Medicine, New York, NY 10021
* To whom correspondence should be addressed. E-mail: garabm01{at}med.nyu.edu.
The Mediator subunits MED14 and MED1 have been implicated in transcriptional regulation by the glucocorticoid receptor by acting through its activation function (AF) 1 and AF2. To understand the contribution of these Mediator subunits to GR gene-specific regulation, we reduced the level of MED14 and MED1 using small interfering RNAs in U2OS-hGR osteosarcoma cells and examined the mRNA induction by dexamethasone of four primary GR target genes, interferon regulatory factor 8 (IRF8), ladinin 1 (LAD1), insulin growth factor binding protein 1 (IGFBP1), and glucocorticoid inducible leucine zipper (GILZ). We found that the GR target genes differed in their requirement for MED1 and MED14. GR-dependent mRNA expression of LAD1 and IRF8 required both MED1 and MED14, whereas induction of IGFBP1 mRNA by the receptor was dependent upon MED14, but not MED1. In contrast, GILZ induction by GR was largely independent of MED1 and MED14, but required the p160 cofactor TIF2. Interestingly, we observed higher GR occupancy at GILZ than at the IGFBP1 or IRF8 GREs. In contrast, recruitment of MED14 relative to GR at IGFBP1 and IRF8 was higher than that observed at GILZ. At GILZ, GR and RNA polymerase II were recruited to both the GRE and the promoter, whereas at IGFBP1, RNA polymerase II occupied the promoter, but not the GRE. Thus, MED14 and MED1 are used by GR in a gene-specific manner, and the requirement for the Mediator at GILZ may be bypassed by increased GR and RNA polymerase II occupancy at the GREs. Our findings suggest that modulation of the Mediator subunit activities would provide a mechanism for promoter selectivity by GR.
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