CHARACTERIZATION OF BRX, A NOVEL DBL FAMILY MEMBER THAT MODULATES ESTROGEN-RECEPTOR ACTION

Regulation of gene activation by the estrogen receptor (ER) is complex and involves co-regulatory proteins, oncoproteins (such as Fos and Ju n), and phosphorylation signaling pathways. Here we report the cloning and initial characterization of a novel protein, Err, that contains a region of identity to the oncogenic Rho-guanine nucleotide exchange ( Rho-GEF) protein Lbc, and a unique region capable of binding to nuclea r hormone receptors, including the ER, Western and immunohistochemistr y studies showed Brx to be expressed in estrogen-responsive reproducti ve tissues, including breast ductal epithelium, Err bound specifically to the ER via an interaction that required distinct regions of ER and Brx. Furthermore, overexpression of Brx in transfection experiments u sing an estrogen-responsive reporter revealed that Err augmented gene activation by the ER in an element-specific and ligand-dependent manne r, Moreover, activation of ER by Brx could be specifically inhibited b y a dominant-negative mutant of Cdc42Hs, but not by dominant negative mutants of RhoA or Rac1. Taken together, these data suggest that Err r epresents a novel modular protein that may integrate cytoplasmic signa ling pathways involving Rho family GTPases and nuclear hormone recepto rs.