Abstract

The proposed studies focus on the mechanisms and consequences of the interaction of ER with 3 nuclear receptor interacting proteins, the corepressors BRCA1 and N-CoR and the coactivator CBP.
Aim 1 is to map the binding regions in the ER LBD for these factors using a battery of ER LBD mutants.
Aim 2 will determine the regions of these coactivators and corepressors that interact with the ER LBD. Synthetic peptides or recombinant proteins will be used in co-crystal structure determinations to investigate the structure of the ER LBD and ER DBD-LBD complexes.
Aim 3 will establish the physiological role of the interaction of BRCA1 with the ER LBD in mammary gland and prostate. Homologous recombination will be used to create mice bearing mutations in the ER LBD that specifically block interactions with BRCA1. The primary tissues to be examined include the mammary gland, ovary, and prostate.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK051083-07
Application #
6524230
Study Section
Biochemical Endocrinology Study Section (BCE)
Program Officer
Margolis, Ronald N
Project Start
1996-08-01
Project End
2004-07-31
Budget Start
2002-08-01
Budget End
2003-07-31
Support Year
7
Fiscal Year
2002
Total Cost
$222,766
Indirect Cost

  Institution

Name
University of California San Francisco
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
073133571
City
San Francisco
State
CA
Country
United States
Zip Code
94143

  Publications

Webb, Paul; Nguyen, Phuong; Kushner, Peter J (2003) Differential SERM effects on corepressor binding dictate ERalpha activity in vivo. J Biol Chem 278:6912-20
Lopez, G N; Turck, C W; Schaufele, F et al. (2001) Growth factors signal to steroid receptors through mitogen-activated protein kinase regulation of p160 coactivator activity. J Biol Chem 276:22177-82
Feng, W; Webb, P; Nguyen, P et al. (2001) Potentiation of estrogen receptor activation function 1 (AF-1) by Src/JNK through a serine 118-independent pathway. Mol Endocrinol 15:32-45
Webb, P; Nguyen, P; Valentine, C et al. (2000) An antiestrogen-responsive estrogen receptor-alpha mutant (D351Y) shows weak AF-2 activity in the presence of tamoxifen. J Biol Chem 275:37552-8
Pissios, P; Tzameli, I; Kushner, P et al. (2000) Dynamic stabilization of nuclear receptor ligand binding domains by hormone or corepressor binding. Mol Cell 6:245-53
Lopez, G N; Webb, P; Shinsako, J H et al. (1999) Titration by estrogen receptor activation function-2 of targets that are downstream from coactivators. Mol Endocrinol 13:897-909
Webb, P; Nguyen, P; Valentine, C et al. (1999) The estrogen receptor enhances AP-1 activity by two distinct mechanisms with different requirements for receptor transactivation functions. Mol Endocrinol 13:1672-85
Ma, H; Hong, H; Huang, S M et al. (1999) Multiple signal input and output domains of the 160-kilodalton nuclear receptor coactivator proteins. Mol Cell Biol 19:6164-73
An, J; Ribeiro, R C; Webb, P et al. (1999) Estradiol repression of tumor necrosis factor-alpha transcription requires estrogen receptor activation function-2 and is enhanced by coactivators. Proc Natl Acad Sci U S A 96:15161-6
Ding, X F; Anderson, C M; Ma, H et al. (1998) Nuclear receptor-binding sites of coactivators glucocorticoid receptor interacting protein 1 (GRIP1) and steroid receptor coactivator 1 (SRC-1): multiple motifs with different binding specificities. Mol Endocrinol 12:302-13

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