Distinct roles of unliganded and liganded estrogen receptors in transcriptional repression.
The decline in estrogen levels during menopause is associated with increased cytokine production and inflammatory diseases. Estrogens exert anti-inflammatory effects by repressing cytokine genes, such as tumor necrosis factor-alpha (TNFalpha). The mechanisms involved in transcriptional repression by estrogens are virtually unknown. Here, we used chromatin immunoprecipitation to investigate how estrogens repress the autoinduction of the TNFalpha gene. TNFalpha assembled a transcriptional activation complex at the TNFalpha promoter that includes c-jun, p50-NFkappaB, p65-NFkappaB, CBP, Hsp90, and unliganded estrogen receptor (ER). Estradiol repressed TNFalpha gene expression by reversing the ligand-independent activation by ERalpha and the stimulatory actions of c-jun, NFkappaB, and CBP on transcription. Silencing of GRIP1 reversed the repression of TNFalpha and other cytokine genes by estradiol, demonstrating that GRIP1 is required for transcriptional repression and can act as a corepressor. Our study demonstrates that ERalpha is a TNFalpha-induced coactivator that becomes a repressor in the presence of estradiol by recruiting GRIP1.
Department of Obstetrics, Gynecology and Reproductive Sciences, Center for Reproductive Sciences, University of California, San Francisco, California 94143, USA.
Aleksandra
A
Cvoro
Christina
C
Tzagarakis-Foster
Deirdre
D
Tatomer
Sreenivasan
S
Paruthiyil
Mark S
MS
Fox
Dale C
DC
Leitman
D050882:CREB-Binding Protein / Q000235:genetics / Q000378:metabolism; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D047628:Estrogen Receptor alpha / Q000378:metabolism*; D004967:Estrogens / Q000378:metabolism*; D005786:Gene Expression Regulation; D018841:HSP90 Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism; D008024:Ligands; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D011401:Promoter Regions, Genetic; D014158:Transcription, Genetic; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics* / Q000378:metabolism
D002352:Carrier Proteins; D016207:Cytokines; D047628:Estrogen Receptor alpha; D004967:Estrogens; C491310:GRIP1 protein, human; D018841:HSP90 Heat-Shock Proteins; D008024:Ligands; D016328:NF-kappa B; D009419:Nerve Tissue Proteins; D014409:Tumor Necrosis Factor-alpha; D050882:CREB-Binding Protein; D048031:JNK Mitogen-Activated Protein Kinases