Inhibition of Estrogen Receptor Action by the Orphan Receptors, SHP and DAX-1
Abstract
In support of DoD grant # DAMD17-99-1-9163, we present our progress towards understanding the function of mechanisms of action of two orphan nuclear receptors, SHP and DAX-I as inhibitors of ER alpha and ER beta action. Consistent with prior studies of SHP, we show that Dax-1 binds directly to ER alpha and ER beta in an agonist dependent manner. In addition we show that this interaction is sufficient to abrogate transcriptional activation of reporter plasmids by ER alpha and ER beta in a manner that is dose dependent. Mapping of this interaction showed that a 90 amino acid region of DAX-1 was sufficient to interact with agonist bound ER alpha and ER beta. This region contains two LXXLL motifs similar to the LXXLL motifs found in ligand-dependent co-activators of the SRC-1 family. Consistent with this, a peptide containing LHRLL from the second NR Box of GRIP one was able to compete away the interaction between ER and this 90 amino acid fragment. This suggests that the mechanism by which DAX-1 interacts with ER alpha and ER beta is similar to the interaction of agonist bound ER and the SRC-1 family of nuclear receptor co-activators. Additionally, over-expression of SRC-1 was sufficient to override the repression of ER activity by DAX-1. Taken together, these data support a model of ligand-dependent transcriptional repression by DAX-1 that is mediated by competition with and displacement of transcriptional co-activators of SRC-l family.
Document Details
- Document Type
- Technical Report
- Publication Date
- Sep 01, 2002
- Accession Number
- ADA412765
Entities
People
- James Direnzo
Organizations
- Dartmouth College