Human Progesterone A-Form as a Target for new Drug Discovery in Human Breast Cancer
Abstract
In humans, the progesterone receptor exists as two isoforms, hPR-A and hPR-B. hPR-B is transcriptionally active, while hPR-A is inactive and acts as a transdominant repressor of estrogen receptor (ER) transcriptional activity. Although, the precise mechanism of hPR-A transrepression is not fully understood, we identified a domain located within the amino terminus of hPR-A, necessary for transrepression. This domain is contained within both PR isoforms, however, its activity is manifested only in hPR-A, suggesting that hPR-A interacts with a set of cofactors that are distinct from those recognized by hPR-B. In support of this hypothesis, we found that the interaction of hPR- A with the corepressor SMRT is stronger than that observed with hPR-B. The importance of such interaction, is demonstrated by using a dominant negative variant of SMRT to partially reverse hPR- A transrepression of ER activity, implicating SMRT in the transrepression by hPR-A. In addition, we show that hPR-B, but not hPR-A, interacts efficiently with the coactivators SRC-l and GRIP 1. Thus, the inability of hPR-A, in contrast to hPR-B, to recruit coactivators, as well as its strong association with corepressor proteins, correlates with the differences in the transcriptional activities of the two
Document Details
- Document Type
- Technical Report
- Publication Date
- Jul 01, 1999
- Accession Number
- ADB258945
Entities
People
- Paloma H. Giangrande
Organizations
- Duke University Hospital