Activated glucocorticoid receptor interacts with the INHAT component Set/TAF-Ibeta and releases it from a glucocorticoid-responsive gene promoter, relieving repression: implications for the pathogenesis of glucocorticoid resistance in acute undifferentiated leukemia with Set-Can translocation.
Set/template-activating factor (TAF)-Ibeta, part of the Set-Can oncogene product found in acute undifferentiated leukemia, is a component of the inhibitor of acetyltransferases (INHAT) complex. Set/TAF-Ibeta interacted with the DNA-binding domain of the glucocorticoid receptor (GR) in yeast two-hybrid screening, and repressed GR-induced transcriptional activity of a chromatin-integrated glucocorticoid-responsive and a ... natural promoter. Set/TAF-Ibeta was co-precipitated with glucocorticoid response elements (GREs) of these promoters in the absence of dexamethasone, while addition of the hormone caused dissociation of Set/TAF-Ibeta from and attraction of the p160-type coactivator GRIP1 to the promoter GREs. Set-Can fusion protein, on the other hand, did not interact with GR, was constitutively co-precipitated with GREs and suppressed GRIP1-induced enhancement of GR transcriptional activity and histone acetylation. Thus, Set/TAF-Ibeta acts as a ligand-activated GR-responsive transcriptional repressor, while Set-Can does not retain physiologic responsiveness to ligand-bound GR, possibly contributing to the poor responsiveness of Set-Can-harboring leukemic cells to glucocorticoids.
Mesh Terms:
Animals, Chromatin Immunoprecipitation, Chromosomal Proteins, Non-Histone, Drug Resistance, Neoplasm, Gene Expression Regulation, Neoplastic, Glucocorticoids, HCT116 Cells, Histone Acetyltransferases, Histone Chaperones, Humans, Leukemia, Ligands, Models, Genetic, Nuclear Proteins, Oncogene Proteins, Fusion, Phosphoproteins, Promoter Regions, Genetic, Protein Binding, Protein Structure, Tertiary, Rats, Receptors, Glucocorticoid, Repressor Proteins, Response Elements, Transcription Factors, Transcription, Genetic, Translocation, Genetic
Animals, Chromatin Immunoprecipitation, Chromosomal Proteins, Non-Histone, Drug Resistance, Neoplasm, Gene Expression Regulation, Neoplastic, Glucocorticoids, HCT116 Cells, Histone Acetyltransferases, Histone Chaperones, Humans, Leukemia, Ligands, Models, Genetic, Nuclear Proteins, Oncogene Proteins, Fusion, Phosphoproteins, Promoter Regions, Genetic, Protein Binding, Protein Structure, Tertiary, Rats, Receptors, Glucocorticoid, Repressor Proteins, Response Elements, Transcription Factors, Transcription, Genetic, Translocation, Genetic
Mol. Cell. Endocrinol.
Date: Feb. 13, 2008
PubMed ID: 18096310
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