Nuclear receptor coactivators

A small number of proteins, including NCoR and SMRT, comprise the corepressor family. They function, at least in part, as described in Figure 43-2. Another family includes the TRAPs, DRIPs, and ARC (Table 43-6). These so-called mediator-related proteins range in size from 80 kDa to 240 kDa and are thought to be involved in linking the nuclear receptor-coactivator complex to RNA polymerase II and the other components of the basal transcription apparatus. 

Among the proteins that form part of the transcription machinery are found some cell factors that are produced in limited quantities. They are called cofactors of transcription (NCoA, for nuclear-receptor coactivator NCoI, for nuclear-receptor coinhibitor), formerly known as transcription intermediary factors (TIF) (McDonnell et al. 2002 McKenna et al. 1999). They constitute one of the classes of proteins that form part of the transcription machinery. These proteins are utilized by diverse types of intensifiers, that is to say, by sequences of DNA that anchor transcription factors, of which HRE are a particular case (Gruber et al. 2002 Mester et al. 1995). They do not interact directly with the DNA, but they do with the receptors and with the other elements of the transcription apparatus (Fig. 1.9). 

McKenna NJ, Xu J, Nawasz Z, Tsai SY, O Malley BW (1999) Nuclear receptor coactivators multiple enzymes, multiple complexes, multiple functions. J Steroid Biochem Mol Biol 69 3-12... 

Carapeti M, Aguiar RC, Goldman JM, Cross NC (1998) A novel fusion between MOZ and the nuclear receptor coactivator TIF2 in acute myeloid leukemia. Blood 91 3127—3133 Chaffanet M, Gressin L, Preudhomme C, Soenen-Comu V, Bimbaum D, Pebusque MJ (2000) MOZ is fused to p300 in an acute monocytic leukemia with t(8 22). Genes Chromosomes. Cancer 28 138—144... 

PRMTl, a nuclear receptor coactivator, exists as in a 330 kDa complex and is a H4 Arg-3 methyltransferase [133,215]. The enzyme appears to be a chromatin bound, and evidence from immunodepletion and knockout studies suggest that it is the principle, if not sole, H4 Arg-3 methyltransferase [133,215]. Mutation of the S-adenosyl methionine binding site in PRMTl annihilated its nuclear receptor coactivator activity with the androgen receptor, providing evidence for the importance of the methylation event in gene expression [215]. Yeast Rmtl, which is homologous to human PRMTl, methylates Arg-3 only in free H4 [208]. 

Glass,C.K., Rose,D.W. and Rosenfeld, M.G (1997) Nuclear receptor coactivators Curr. Op. Cell Biol. 9, 222.232... 

Darimont BD, et al. Structure and specificity of nuclear receptor-coactivator interactions. Genes Dev. 1998 12 3343-3356. 

Heery DM, et al. A signature motif in transcriptional co-activators mediates binding to nuclear receptors. Nature 1997 387 733-736. Glass CK, Rose DW, Rosenfeld MG. Nuclear receptor coactivators. Curr. Opin. Cell Biol. 1997 9 222-2232. 

Glass CK, Rose DW, Rosenfeld MG. Nuclear receptor coactivators. 

T.N. Collingwood, F.D. Umov, and A.P. Wolffe. 1999. Nuclear receptors Coactivators, corepressors and chromatin remodeling in the control of transcription J. Mol. Endocrinol. 23 255-275. (PubMed)... 

Blanco JCG, Minucci S, Lu J, Yang XJ, WalkerKK,etal. 1998. The histone acety-lase PCAF is a nuclear receptor coactivator. Genes Dev. 12 1638-51... 

Chen H, Lin RJ, Schiltz RL, Chakravarti D, Nash A, et al. 1997. Nuclear receptor coactivator ACTR is a novel his-... 

Yang W, Rachez C, Freedman LP. 2000. Discrete roles for peroxisome proliferator-activated receptor gamma and retinoid X receptor in recruiting nuclear receptor coactivators. Mol. Cell. Biol. 20 8008-17... 

Horwitz, K. B., Jackson, T. A., Bain, D. L., Richer, 1. K., Takimoto, G. S., and Tung, L. (1996). Nuclear receptor coactivators and corepressors. Mol Endocrinol 10, 1167—1177. lARC (1999). Hormonal contraception and post-menopausal hormonal therapy. In Cancer of the Liver and Gall-bladder, Vol. 72, lARC Monographs, lARC Press, Lyon, pp. 168—180. 

For many specific transcriptional activators, the recruitment of histone acetylase activity and a subsequent reorganization of chromatin has been identified as an essential step in transcription activation of chromatin-covered DNA (see Section 1.4.6). The identification of nuclear receptor coactivators with direct or associated histone acetylase activity underscores that nuclear receptors use the recruitment of histone acetylase as an essential step in transcription activation as well. The association of various various histone acetylase activites with the coactivators of the nuclear receptors indicates that distinct protein complexes with HAT activity can be recruited to DNA-bound nuclear receptors. It is still an open issue which specific functions are performed by the different HAT activities during transcription activation. 

In addition to the receptors themselves, the nuclear receptor coactivators have also been found to be targets of regulatory phosphorylation events. 

In this chapter we discuss both the insight that has been gained concerning the biological relevance of inhibiting the nuclear receptor-coactivator interaction and the progress made in the development of inhibitors for this interaction. The biological... 

Cyclization of peptides is an established strategy to stabilize short peptides in an a-helical conformation. Concomitantly, different types of cyclic peptides have been explored as inhibitors of the nuclear receptor-coactivator interaction. Guy et al. have created a library of a-helical constrained peptidomimetics, based on the second nuclear receptor box found in the SRC2 coactivator, by the introduction of a macrolactam bridge [56-58]. The macrolactam bridge induces an a-helical... 

The nuclear receptor-cofactor interaction, more specifically the nuclear receptor-coactivator interaction, has emerged as a drugable protein-protein interaction. Even though many aspects of its drugability are still unsolved, both the results obtained on the biological evaluation of its direct inhibition and the development of the first small-molecule inhibitors show the potential of targeting this interaction. 

The first CBIs have been published recently and, considering the limited amount of optimization work performed on these compounds thus far, their moderate affinity holds great promise for significant improvement. As such, these compounds provide a very good basis for optimization, proof-of-concept and selectivity studies. Independent of the ultimate biological validity ofthese compounds, these recent studies show that small molecules can be found that inhibit the nuclear receptor-coactivator interaction. 

The current studies on inhibiting the nuclear receptor-coactivator interaction have focused mainly on the ERs, AR and TR. With compounds developed against these nuclear receptors it becomes possible to also target other nuclear receptors (e.g. the orphan nuclear receptors). Here, CBIs might provide an entry for modulation of these nuclear receptors for which up to now no classical ligand has been found. 

Fowlkes, D. and McDonnell, D.P. (1999) Dissection of the LXXLL nuclear receptor— coactivator interaction motif using combinatorial peptide libraries discovery of peptide antagonists of estrogen receptors a and p. Molecular and Cellular Biology, 19, 8226-8239. 

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