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 Jun), and phosphorylation signaling pathways. Here we report the cloning and initial characterization of a novel protein, Brx, 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 nuclear hormone receptors, including the ER. Western and immunohistochemistry studies showed Brx to be expressed in estrogen-responsive reproductive tissues, including breast ductal epithelium. Brx bound specifically to the ER via an interaction that required distinct regions of ER and Brx. Furthermore, overexpression of Brx in transfection experiments using an estrogen-responsive reporter revealed that Brx augmented gene activation by the ER in an element-specific and ligand-dependent manner. Moreover, activation of ER by Brx could be specifically inhibited by a dominant-negative mutant of Cdc42Hs, but not by dominant negative mutants of RhoA or Rac1. Taken together, these data suggest that Brx represents a novel modular protein that may integrate cytoplasmic signaling pathways involving Rho family GTPases and nuclear hormone receptors.
Rubino
D
D
Office of the Scientific Director, National Institute of Child Health and Human Development, and DEB, National Institutes of Health, Bethesda, Maryland 20892, USA.
Driggers
P
P
Arbit
D
D
Kemp
L
L
Miller
B
B
Coso
O
O
Pagliai
K
K
Gray
K
K
Gutkind
S
S
Segars
J
J
D054758:A Kinase Anchor Proteins; D048868:Adaptor Proteins, Signal Transducing; D000595:Amino Acid Sequence; D000818:Animals; D001940:Breast / Q000378:metabolism / Q000473:pathology; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D003001:Cloning, Molecular; D018076:DNA, Complementary; D005260:Female; D019204:GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism; D020662:Guanine Nucleotide Exchange Factors; D006801:Humans; D008297:Male; D015778:Minor Histocompatibility Antigens; D008969:Molecular Sequence Data; D016296:Mutagenesis; D015513:Oncogene Proteins / Q000145:classification / Q000235:genetics / Q000378:metabolism*; D011518:Proto-Oncogene Proteins; D011817:Rabbits; D011960:Receptors, Estrogen / Q000378:metabolism* / Q000502:physiology; D015682:Retroviridae Proteins, Oncogenic; D017386:Sequence Homology, Amino Acid; D013737:Testis / Q000276:immunology / Q000473:pathology; D014018:Tissue Distribution; D014407:Tumor Cells, Cultured; D020764:cdc42 GTP-Binding Protein
D054758:A Kinase Anchor Proteins; C085467:AKAP13 protein, human; D048868:Adaptor Proteins, Signal Transducing; D018797:Cell Cycle Proteins; D018076:DNA, Complementary; D020662:Guanine Nucleotide Exchange Factors; C057811:MCF2 protein, human; D015778:Minor Histocompatibility Antigens; D015513:Oncogene Proteins; D011518:Proto-Oncogene Proteins; D011960:Receptors, Estrogen; D015682:Retroviridae Proteins, Oncogenic; D019204:GTP-Binding Proteins; D020764:cdc42 GTP-Binding Protein