Abstract
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.
Publication types
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Research Support, N.I.H., Intramural
MeSH terms
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Animals
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Chromatin Immunoprecipitation
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Chromosomal Proteins, Non-Histone / genetics
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Chromosomal Proteins, Non-Histone / metabolism*
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DNA-Binding Proteins
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Drug Resistance, Neoplasm / drug effects
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Gene Expression Regulation, Neoplastic / drug effects
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Glucocorticoids / pharmacology*
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HCT116 Cells
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Histone Acetyltransferases / metabolism
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Histone Chaperones
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Humans
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Leukemia / pathology*
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Ligands
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Models, Genetic
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Nuclear Proteins / metabolism
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Oncogene Proteins, Fusion / metabolism*
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Phosphoproteins / metabolism
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Promoter Regions, Genetic / genetics*
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Protein Binding / drug effects
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Protein Structure, Tertiary
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Rats
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Receptors, Glucocorticoid / chemistry
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Receptors, Glucocorticoid / genetics
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Receptors, Glucocorticoid / metabolism*
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Repressor Proteins / metabolism
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Response Elements
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Transcription Factors / genetics
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Transcription Factors / metabolism*
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Transcription, Genetic / drug effects
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Translocation, Genetic* / drug effects
Substances
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Chromosomal Proteins, Non-Histone
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DNA-Binding Proteins
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Glucocorticoids
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Histone Chaperones
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Ligands
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Nuclear Proteins
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Oncogene Proteins, Fusion
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Phosphoproteins
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Receptors, Glucocorticoid
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Repressor Proteins
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SET protein, human
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SET-CAN fusion protein, human
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Transcription Factors
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Histone Acetyltransferases