Nuclear receptors enhancer

The strict control of the activity of nuclear receptors by their respective ligands has recently permitted to follow the dynamics of DNA occupancy and to discover a surprising feature, which may be true also for other enhancer-binding factors. During transcriptional activation these transcription factors do not stably reside... 

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. 

Sugatani J, Kojima H, Ueda A et al (2001) The phenobarbital response enhancer module in the human bilirubin UDP-glucuronosyltransferase UGT1A1 gene and regulation by the nuclear receptor CAR. Hepatology 33 1232-1238... 

Bile helps in the digestion and absorption of fats. Its constituent bile acids (BAs) have detergent properties, and some can be carcinogenic. BAs can act as signalling molecules, entering the nuclei and reacting with the nuclear receptors and this could enhance or reduce BA synthesis. In this way, they control their own levels as well as those of their precursor, cholesterol. This controls cholesterol homeostasis and BA and lipid synthesis. 

Cis-acting DNA elements can he near the start site of transcription or be quite distanced from it. Fmthermore, there are examples among eucaryotes in which the cis element is foimd within the transcribed region. If the cis element is located far from the site of action and its effect is also orientation-independent, then it is termed an enhancer. Fmthermore, one frequently observes in eucaryotes so called composite control regions which contain various cis elements. In this case, several transcription factors act cooperatively in the initiation of transcription. Examples for such cooperative effects are observed among the genes controlled by nuclear receptors. 

Figure 5.34 Mechanism of induction of CYP2B6 by a chemical such as the drug phenobarbital. This drug activates a nuclear receptor (CAR).This combines with the retinoid X receptor and binds to PBREM, as specific section of the CYP gene, which stimulates the production of CYP2B6 mRNA leading to the production of CYP2B6 protein and enzyme. Abbreviations CAR, constitutive androstane receptor RXR retinoid X receptor PBREM, phenobarbital-responsive enhancer module.

Figure 9.10 Illustration depicting DNA elements found in CYP3A genes and the activation of the human pregnane X receptor (PXR) by ligand (RIF) and subsequent transcriptional activation of CYP3A4 gene by the PXR/RXR heterodimer. dNR-1-3, nuclear receptors 1, 2, and 3, respectively PXR, pregnane X receptor RXR, retinoid X receptor RIF, rifampicin SRC-1, steroid receptor co-activator XREM, xenobiotic responsive enhancer module.

Exposure to a ligand (such as TCDD) enhances (i.e., induces) expression of the AhR gene and activates a diverse battery of other genes including CYP1A1. Variability in Ah activity has been studied extensively in animal models, and it is clear that AhR induction by arylhydrocarbons is central to understanding the pharmacogenetics of nuclear receptors (106-108). This topic is more appropriately dealt with in detail elsewhere (see Chapter 2d, Variability of induction processes, A. Okey). 

Makinen J, Frank C, Jyrkkarinne J, Gynther J, Carlberg C, Flonkakoski P. Modulation of mouse and human phenobarbital-responsive enhancer module by nuclear receptors. Mol Pharmacol 2002 62 366-378. 

Our observations suggest that Ser-106 and Ser-124 are both required in vivo to fully recruit SRC-1. In addition, when cells were treated with factors known to activate Ras, such as EGF or IGF-1 (data not shown), the in vivo interaction between SRC-1 and ER(3 was also enhanced, thus mimicking the results obtained in the presence of activated Ras. This study demonstrates for the first time that phosphorylation of the AF-1 domain of a member of the nuclear receptor superfamily enhances the recruitment of a steroid receptor coactivator (SRC-1) and provides a molecular basis for ligand-independent activation of ER(3 via the MAPK cascade. 

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