Ligand-dependent repression of the erythroid transcription factor GATA-1 by the estrogen receptor.
High-dose estrogen administration induces anemia in mammals. In chickens, estrogens stimulate outgrowth of bone marrow-derived erythroid progenitor cells and delay their maturation. This delay is associated with down-regulation of many erythroid cell-specific genes, including alpha- and beta-globin, band 3, band 4.1, and the erythroid cell-specific histone H5. We show here that estrogens also reduce the number of erythroid progenitor cells in primary human bone marrow cultures. To address potential mechanisms by which estrogens suppress erythropoiesis, we have examined their effects on GATA-1, an erythroid transcription factor that participates in the regulation of the majority of erythroid cell-specific genes and is necessary for full maturation of erythrocytes. We demonstrate that the transcriptional activity of GATA-1 is strongly repressed by the estrogen receptor (ER) in a ligand-dependent manner and that this repression is reversible in the presence of 4-hydroxytamoxifen. ER-mediated repression of GATA-1 activity occurs on an artificial promoter containing a single GATA-binding site, as well as in the context of an intact promoter which is normally regulated by GATA-1. GATA-1 and ER bind to each other in vitro in the absence of DNA. In coimmunoprecipitation experiments using transfected COS cells, GATA-1 and ER associate in a ligand-dependent manner. Mapping experiments indicate that GATA-1 and the ER form at least two contacts, which involve the finger region and the N-terminal activation domain of GATA-1. We speculate that estrogens exert effects on erythropoiesis by modulating GATA-1 activity through protein-protein interaction with the ER. Interference with GATA-binding proteins may be one mechanism by which steroid hormones modulate cellular differentiation.
Blobel
G A
GA
Division of Hematology/Oncology, Children's Hospital, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA.
Sieff
C A
CA
Orkin
S H
SH
D000818:Animals; D001853:Bone Marrow / Q000378:metabolism; D002452:Cell Count; D002478:Cells, Cultured; D002645:Chickens; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015672:Erythroid Precursor Cells / Q000166:cytology / Q000187:drug effects; D050981:Erythroid-Specific DNA-Binding Factors; D004967:Estrogens / Q000494:pharmacology*; D050982:GATA1 Transcription Factor; D006801:Humans; D011960:Receptors, Estrogen / Q000378:metabolism*; D014157:Transcription Factors / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects
D004268:DNA-Binding Proteins; D050981:Erythroid-Specific DNA-Binding Factors; D004967:Estrogens; D050982:GATA1 Transcription Factor; C494688:GATA1 protein, human; D011960:Receptors, Estrogen; D014157:Transcription Factors