Estrogen (E) affects both reproductive and non-reproductive functions, which are mainly mediated by the estrogen receptor (ER). Two ER isoforms, alpha and beta, share high structural homology, but display diverse transcriptional activities in response to E. In the presence of E, ligand-bound ER undergoes a rapid degradation through the ubiquitin-proteasome pathway, and this ER degradation tightly couples with its transcriptional activity. In addition, without E, ER can also be activated by cAMP-dependent protein kinase (PKA), and this E-independent ER activation may play an important role in the neuroendocrine system. Therefore, my long-term research objective is to elucidate the mechanisms by which PKA activates ER and the relevance to both physiology and disease. The interim goal for the current proposal will concentrate on understanding how the two ER isoforms can respond differently to the stimulation of forskolin (FSK) that activates PKA.
Two specific aims will be examined: (1) identify specific region(s) residing in the rat ER alpha that mediate the FSK-induced ER activation; (2) test whether the specific FSK-responsive region(s) on rat ER alpha are required for maintaining ER alpha from degradation by the ubiquitin-proteasome pathway. The results of these studies should increase our understanding the molecular mechanisms for the E-independent activation of ER, and how this activation is linked to degradation.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
5F32DK064548-02
Application #
6859373
Study Section
Special Emphasis Panel (ZRG1-F06 (20))
Program Officer
Hyde, James F
Project Start
2003-09-01
Project End
2005-08-31
Budget Start
2004-09-01
Budget End
2005-08-31
Support Year
2
Fiscal Year
2004
Total Cost
$48,928
Indirect Cost
Name
University of Virginia
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
065391526
City
Charlottesville
State
VA
Country
United States
Zip Code
22904