Nuclear receptor corepressor

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. 

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). 

Fig. 7. Model for activation by coactivators (A) and inhibition by corepressors (B) of transcription. Abbreviations CBP/p300, cAMP response element binding protein SRC-1, steroid receptor coactivator 1 TBP, TATA-binding protein TAF, TBP-associated factor pol II, RNA polymerase II N-CoR, nuclear receptor corepressor SMRT, silencing mediator of retinoic and thyroid hormone receptors.

Horlein AJ, Naar AM, Heinzel T, Torchia J, Gloss B, et al. 1995. Ligand-independent repression by the thyroid hormone receptor mediated by a nuclear receptor corepressor. Nature 377 397-404... 

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... 

White R, Leonardsson G, Rosewell I, Jacobs MA, Milligan S, Parker MG. 2000. The nuclear receptor corepressor Nripl (RIP140) is essential for female fertility. Nat. Med. 6 1368-74... 

Liu, M. H., Li, J., Shen, R, Husna, B., Tai, E. S., and Yong, E. L. (2008). A natural polymorphism in peroxisome proliferator-activated receptor-alpha hinge region attenuates transcription due to defective release of nuclear receptor corepressor from chromatin. Mol Endocrinol 22, 1078-1092. 

Balk, S.P. and Hollenberg, A.N. (2005) The androgen receptor recruits nuclear receptor corepressor (N-CoR) in the presence of mifepristone via its N and C termini revealing a novel molecular mechanism for androgen receptor antagonists. The Journal of Biological Chemistry, 280, 6511-6519. 

Blaschke, F., Takata, Y., Caglayan, E., Collins, A.,Tontonoz, P., Hsueh, W.A. and Tangirala, R.K. (2006) A nuclear receptor corepressor-dependent pathway mediates suppression of cytokine-induced C-reactive protein gene expression by liver X receptor. Circulation Research, 99, e88-e99. 

Johnson, D. R., Li, C. W., Chen, L. Y., Ghosh, J. C., and Chen, J. D. (2006) Regulation and binding of pregnane X receptor by nuclear receptor corepressor silencing mediator of retinoid and thyroid hormone receptors (SMRT). Mol. Pharmacol. 69, 99-108. 

Nuclear Receptor Corepressor in Xenobiotic Receptor Signaling... 

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],... 

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