Transactivation Nuclear receptor

Chromatin remodeling, transcription factor modification by various enzyme activities, and the communication between the nuclear receptors and the basal transcription apparatus are accomplished by protein-protein interactions with one or more of a class of coregulator molecules. The number of these coregulator molecules now exceeds 100, not counting species variations and splice variants. The first of these to be described was the CREB-binding protein, CBP. CBP, through an amino terminal domain, binds to phosphorylated serine 137 of CREB and mediates transactivation in response to cAMP. It thus is described as a coactivator. CBP and... 

The participation of the nuclear receptors in the machinery of gene transcription takes place by means of specific domains of the molecule known as transactivators (abbreviation for transcription activators). These are made up of sequences of amino acids that interact by means of protein-protein contacts with other transcription factors. The artificial alteration of these sequences has as a consequence the inability of the hormone to induce gene expression (Beato et al. 1996 Klug et al. 1987 Lones et al. 1995). 

The other transactivator domain, TAF2, is found immersed in the LBD and acts only when the hormone-receptor complex is formed. A sequence of 15 well-conserved amino acids from the different members of the family of nuclear receptors, and situated very close to the carboxyl end of the receptors, participates in it (Gruber et al. 2002 Nilsson et al. 2001). 

Voegel JJ, Heine MJ, Tini M, Vivat V, Chambon P, Gronemeyer H (1998) The coactivator TIE2 contains three nuclear receptor-binding motifs and mediates transactivation through CBP binding-dependent and -independent pathways. EMBO J 17 507-519... 

Nuclear receptors exert their different transcriptional functions through interactions with and the recruitment of co-factors to responsive promoters. Co-factors are either positive or negative regulatory proteins and are classified as co-activators, which promote, or co-repressors, which attenuate the activity of nuclear hormone receptors [46]. The molecular mechanisms that regulate the mutually exclusive interactions of the nuclear receptor with either class of co-factors have been analysed by crystallographic studies. Functional and structural studies have shown that co-activators interact with the transactivation function (AF) of nuclear hormone receptors via short, leucine-rich motifs (LXXLL) termed NR boxes , thereby transducing hormonal signals to the basal transcription machinery [47]. 

Sundvold H, Lien S 2001 Identification of a novel peroxisome proliferator-activated receptor (PPAR) gamma promoter in man and transactivation by the nuclear receptor RORalphal. Biochem Biophys Res Commun 287 383-390... 

A typical nuclear receptor contains a domain responsible for the DNA binding (domain C), the ligand binding and dimerization (E), and for the transactivation and other protein-protein interactions (A,B,E,F). Furthermore, there are also nuclear localization signals (D). 

The Ugand binding domain (section E in fig. 4.5) of the nuclear receptors harbors several functions. Apart from the specific binding site for the hormone, one finds further structural elements in this domain which mediates dimerization of the receptors as well as structural elements important for the ligand-mediated transactivation. 

No functional polymorphisms have been reported in human CAR, the major nuclear receptor that mediates CYP2B6 induction. However, PXR, which also plays a significant role in CYP2B6 induction, exists as multiple allelic variants, some of which alter transactivation function of this receptor (122,123). 

Dahlman-Wright K, et al. Dehneation of a small region within the major transactivation domain of the human glucocorticoid receptor that mediates transactivation of gene expression. Proc. Natl. Acad. Sci. U.S.A. 1994 91 1619-1623. Hadzopoulou-Cladaras M, et al. Functional domains of the nuclear receptor hepatoc)4e nuclear factor 4. J. Biol. Chem. 1997 272 539-550. 

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