Abstract

The overall goal of this renewal application is to define the mechanism(s) of gene transcription by the vitamin D3 receptor (VDR). To do so, VDR will be described structurally in the context of its actions as both a transcriptional repressor and activator. The role of a newly discovered coactivator complex, called DRIP, that is recruited to nuclear receptors in a ligand-dependent manner and is required by VDR to elicit transcriptional activation at a promoter, will also defined functionally. The overall goals are to apply the information generated here to increase our knowledge of how nuclear receptors regulate gene transcription in response to hormones.
The specific aims are: 1) To determine the structure of VDR in transactivating and transrepressing conformations; 2) To generate reagents required for the study of DRIP function in vivo and in vitro; 3) To define the mechanisms of VDR transactivation through coactivators, and 4) To define the mechanism of VDR-mediated coactivation on a complex promoter.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
2R37DK045460-09
Application #
6196136
Study Section
Endocrinology Study Section (END)
Program Officer
Margolis, Ronald N
Project Start
1992-09-30
Project End
2005-08-31
Budget Start
2000-09-01
Budget End
2001-08-31
Support Year
9
Fiscal Year
2000
Total Cost
$291,375
Indirect Cost

  Institution

Name
Sloan-Kettering Institute for Cancer Research
Department
Type
DUNS #
064931884
City
New York
State
NY
Country
United States
Zip Code
10065

  Publications

Gamble, Matthew J; Fisher, Robert P (2007) SET and PARP1 remove DEK from chromatin to permit access by the transcription machinery. Nat Struct Mol Biol 14:548-55
Larochelle, Stephane; Batliner, Jasmin; Gamble, Matthew J et al. (2006) Dichotomous but stringent substrate selection by the dual-function Cdk7 complex revealed by chemical genetics. Nat Struct Mol Biol 13:55-62
Fisher, Robert P (2005) Secrets of a double agent: CDK7 in cell-cycle control and transcription. J Cell Sci 118:5171-80
Gamble, Matthew J; Erdjument-Bromage, Hediye; Tempst, Paul et al. (2005) The histone chaperone TAF-I/SET/INHAT is required for transcription in vitro of chromatin templates. Mol Cell Biol 25:797-807
Barletta, Frank; Freedman, Leonard P; Christakos, Sylvia (2002) Enhancement of VDR-mediated transcription by phosphorylation: correlation with increased interaction between the VDR and DRIP205, a subunit of the VDR-interacting protein coactivator complex. Mol Endocrinol 16:301-14
Staeva-Vieira, Teodora P; Freedman, Leonard P (2002) 1,25-dihydroxyvitamin D3 inhibits IFN-gamma and IL-4 levels during in vitro polarization of primary murine CD4+ T cells. J Immunol 168:1181-9
Burakov, Darya; Crofts, Linda A; Chang, Chao-Pei Betty et al. (2002) Reciprocal recruitment of DRIP/mediator and p160 coactivator complexes in vivo by estrogen receptor. J Biol Chem 277:14359-62
Maeda, Yutaka; Rachez, Christophe; Hawel 3rd, Leo et al. (2002) Polyamines modulate the interaction between nuclear receptors and vitamin D receptor-interacting protein 205. Mol Endocrinol 16:1502-10
Yang, W; Rachez, C; Freedman, L P (2000) Discrete roles for peroxisome proliferator-activated receptor gamma and retinoid X receptor in recruiting nuclear receptor coactivators. Mol Cell Biol 20:8008-17
Burakov, D; Wong, C W; Rachez, C et al. (2000) Functional interactions between the estrogen receptor and DRIP205, a subunit of the heteromeric DRIP coactivator complex. J Biol Chem 275:20928-34

Showing the most recent 10 out of 27 publications