Histone deacetylase nuclear receptor

The antagonist-induced conformation of nuclear hormone receptors attracts co-repressors like Nco/SMRT (nuclear hormone receptor co-repressor/silencing mediator of retinoid and thyroid receptors) which further recruit other nuclear proteins with histone deacetylase activity. Their action leads to chromatin condensation, thus preventing the general transcription apparatus from binding to promoter regions. 

Beside coactivators so-called corepressors exist that are bound to transcription factors such as nuclear receptors and inhibit the initiation of transcription. These factors include the nuclear receptor corepressor (NCoR) and the silencing mediator of retinoic acid and thyroid hormone receptor (SMRT), which interact with nuclear receptors and serve as platforms for complexes containing histone deacetylases (HDACs). These enzymes cause the reversal of histone acetylation of histones leading to a tightening of chromatin and enhancing its inaccessibility for RNA polymerase containing complexes. 

In the absence of ligand, some nuclear hormone receptors associate with co-repressors, namely, SMRT (silencing mediator of retinoic acid and thyroid hormone receptors) and N-CoR (nuclear receptor co-repressor). Both, SMRT and N-CoR, recruit coregulatory protein SINS and histone deacetylases (HDACs) to form a large co-repressor complex that contains histone deacetylase activity, implicating histone deacetylation in transcriptional repression [52,53]. 

Fig. 4 Co-activator and co-repressor complexes are required for nuclear hormone receptor-mediated transcriptional regulation. The tissue-selective fine-tuning of gene transcription by nuclear hormone receptors is due to different co-regulatory complexes that have various functions and enzymatic activities. Co-activator complexes include factors that contain ATP-dependent chromatin remodelling activity often associated with histone acetyltransferase (HAT) activity. Co-repressors include ATP-dependent chromatin remodelling complexes, which function as platforms for the recruitment of several subcomplexes that often contain histone deacetylase (HDAC) activity...

The histone deacetylases are found in large protein complexes, often together with repressive transcription factors. By this token, interactions of the repressive heterodi-meric transcription factor Mad-Max and a complex with the histone deacetylase HDAC I and the mSinSA protein have been demonstrated. A complex of HDAC I and the nuclear receptor-corepressor (see chapter 4) binds to unliganded nuclear receptors and is believed to exercise a repressive effect. A further example is the tumor suppressor protein pRb (see chapters 13,14), which can occur as a transcription repressor in the hypo-phosphorylated form and transcriptionally activating in the hyperphosphorylated form. The repressive form of the pRb protein recruits the histone deacetylase HDAC 1 to the DNA and thereby initiates an active repression of the gene (see 13.3.2). 

Nagy L, Kao HY, Chakravarti D, Lin RJ, Hassig CA, et al. 1997. Nuclear receptor repression mediated by a complex containing SMRT, mSin3A, and histone deacetylase. Cell 89 373-80... 

Huang EY, Zhang J, Miska EA, Guenther MG, Kouzarides T, Lazar MA. 2000. Nuclear receptor corepressors partner with class II histone deacetylases in a Sin3-independent repression pathway. Genes Dev. 14 45-54... 

Essentially the functional counterpart of coactivators, corepressor proteins bind to many NRs in the absence of ligand and serve to repress basal transcriptive activity [62], Corepressors play a particularly important role for NRs that are found almost exclusively in the nucleus, unlike the apo steroid receptors that are cytoplasmically localized. Studies involving the nuclear-localized receptors TR and RAR led to the identification of silencing mediator of retinoid and thyroid (SMRT) receptors and nuclear receptor corepressor (NCoR) [63, 64]. Both SMRT and NCoR recruit histone deacetylases (HDACs), namely, HDAC3, which function to reverse the chromatin unwinding result of the coactivator-recruited histone acetylases [65],... 

Codina A, Love ID, Li Y, Lazar MA, Neuhaus D, Schwabe JW. Structural insights into the interaction and activation of histone deacetylase 3 by nuclear receptor coreceptors. Proc Natl Acad Sci USA. 2005 102 6009-14. 

There has been a recent explosion of studies regarding the functional activities associated with co-repressor molecules. While originally defined as nuclear receptor co-repressors, we now know that these proteins interact with a variety of factors. N-CoR and SMRT have been characterized as part of a multi-subunit repression complex [49, 50]. Independent of nuclear receptor interaction, N-CoR interacts with mSin3A and B, mammalian homologues of the yeast transcriptional repressor Sin3 [51]. Also in this complex are proteins which exhibit histone deacetylase activity. It has been demonstrated that co-repressor and co-activator molecules are... 

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