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.
Ichijo
Takamasa
T
Section on Pediatric Endocrinology, Reproductive Biology and Medicine Branch, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892-1109, USA.
Chrousos
George P
GP
Kino
Tomoshige
T
D000818:Animals; D047369:Chromatin Immunoprecipitation; D002868:Chromosomal Proteins, Non-Histone / Q000235:genetics / Q000378:metabolism*; D004268:DNA-Binding Proteins; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D005938:Glucocorticoids / Q000494:pharmacology*; D045325:HCT116 Cells; D051548:Histone Acetyltransferases / Q000378:metabolism; D056488:Histone Chaperones; D006801:Humans; D007938:Leukemia / Q000473:pathology*; D008024:Ligands; D008957:Models, Genetic; D009687:Nuclear Proteins / Q000378:metabolism; D015514:Oncogene Proteins, Fusion / Q000378:metabolism*; D010750:Phosphoproteins / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000235:genetics*; D011485:Protein Binding / Q000187:drug effects; D017434:Protein Structure, Tertiary; D051381:Rats; D011965:Receptors, Glucocorticoid / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D012097:Repressor Proteins / Q000378:metabolism; D020218:Response Elements; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic / Q000187:drug effects; D014178:Translocation, Genetic / Q000187:drug effects
D002868:Chromosomal Proteins, Non-Histone; D004268:DNA-Binding Proteins; D005938:Glucocorticoids; D056488:Histone Chaperones; D008024:Ligands; D009687:Nuclear Proteins; D015514:Oncogene Proteins, Fusion; D010750:Phosphoproteins; D011965:Receptors, Glucocorticoid; D012097:Repressor Proteins; C513473:SET protein, human; C481746:SET-CAN fusion protein, human; D014157:Transcription Factors; D051548:Histone Acetyltransferases