Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P05412 (c-Jun)
 11,453 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The mechanisms that control the precisely regulated switch from gene repression to gene activation represent a central question in mammalian development. Here, we report that transcriptional activation mediated by liganded nuclear receptors unexpectedly requires the actions of two highly related F box/WD-40-containing factors, TBL1 and TBLR1, initially identified as components of an N-CoR corepressor complex. TBL1/TBLR1 serve as specific adaptors for the recruitment of the ubiquitin conjugating/19S proteasome complex, with TBLR1 selectively serving to mediate a required exchange of the nuclear receptor corepressors, N-CoR and SMRT, for coactivators upon ligand binding. Tbl1 gene deletion in embryonic stem cells severely impairs PPARgamma-induced adipogenic differentiation, indicating that TBL1 function is also biologically indispensable for specific nuclear receptor-mediated gene activation events. The role of TBLR1 and TBL1 in cofactor exchange appears to also operate for c-Jun and NFkappaB and is therefore likely to be prototypic of similar mechanisms for other signal-dependent transcription factors.
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PMID:A corepressor/coactivator exchange complex required for transcriptional activation by nuclear receptors and other regulated transcription factors. 1498 Feb 19

The nuclear receptor corepressor (NCoR) and the related factor known as silencing mediator of retinoic acid and thyroid hormone receptor (SMRT) are essential components of multiprotein complexes that mediate active repression by unliganded nuclear receptors. Recent studies suggest that NCoR and SMRT can interact with and exert repressive effects on several other classes of DNA-binding transcription factors, but the physiological importance of these interactions has not been established. Here, investigation of endogenous transcriptional programs regulated by NCoR in macrophages reveals that NCoR acts as a transcriptional checkpoint for activator protein (AP)-1-dependent gene networks that regulate diverse biological processes including inflammation, cell migration, and collagen catabolism, with loss of NCoR, resulting in derepression of AP-1 target genes. The NCoR corepressor complex imposes an active block of exchange of c-Jun for c-Jun/c-Fos heterodimers, with targeted deletion of the c-Jun locus, resulting in loss of NCoR complexes from AP-1 target genes under basal conditions. The checkpoint function of NCoR is relieved by signal-dependent phosphorylation of c-Jun, which directs removal of NCoR/HDAC3/TBL1/TBLR1 complexes through recruitment of a specific ubiquitylation complex, as a prerequisite to the default binding of c-Jun/c-Fos heterodimers and transcriptional activation. The requirement for a checkpoint function to achieve the appropriate dynamic range of transcriptional responses to inflammatory signals is likely to be used by other signal-dependent transcription factors that regulate diverse homeostatic and developmental processes.
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PMID:A nuclear receptor corepressor transcriptional checkpoint controlling activator protein 1-dependent gene networks required for macrophage activation. 1545 44