Nuclear receptor-regulated gene

Small molecules constitute the ultimate goal in the search for compounds that can directly block the nuclear receptor-cofactor interaction. Such compounds would not only constitute a new pharmacological and cell biological tool to modulate nuclear receptor-regulated gene transcription, but are also envisaged to provide a new entry in nuclear receptor antagonism. 

Abbott BD, Wood CR, Watkins AM et al (2012) Effects of perfluorooctanoic acid (PFOA) on expression of peroxisome proliferator-activated receptors (PPAR) and nuclear receptor-regulated genes in fetal and postnatal CD-I mouse tissues. Reprod Toxicol 33(4) 491-505 Andersen CS, Fei CY, Gamborg M et al (2010) Prenatal exposures to perfluorinated chemicals and anthropometric measures in infancy. Am J Epidemiol 172(11) 1230-1237 Apelberg B J, Witter ER, Herbstman JB et al (2007) Cord serum concentrations of perfluorooctane sulfonate (PEGS) and perfluorooctanoate (PEOA) in relation to weight and size at birth. Environ Health Perspect 115(11) 1670-1676... 

Nuclear Receptor Regulation of Hepatic Cytochrome P450 Enzymes. Figure 1 General mechanism for transcriptional activation of CYP genes by xenochemicals that activate their cognate xeno-receptor proteins. In the case of Ah receptor, the receptor s heterodimerization partner is Arnt, whereas in the case of the nuclear receptors CAR, PXR, and PPARa, the heterodimerization partner is RXR. The coactivator and basal transcription factor complexes shown are each comprised of a large number of protein components. 

Mammalian nuclear receptors regulate the expression or activation of target genes from promoter sequences that contain either a palindromic or a direct repeat DNA sequence collectively termed hormone response elements (HREs). Most nnclear receptors bind to HREs as either a homodimer... 

Lim YP, Huang JD (2008) Interplay of pregnane X receptor with other nuclear receptors on gene regulation. Drug Metab Pharmacokinet 23(1) 14-21... 

Zhang, Y., Castellani, L. W., Sinai, C. J., Gonzalez, F. J., and Edwards, P. A. (2004) Peroxisome proliferator-activated receptor-gamma coactivator 1 alpha (PGC-1 alpha) regulates triglyceride metabolism by activation of the nuclear receptor FXR. Genes Dev. 18, 157-169. 

Kurokawa, R, Yu, V C., Naar, A., Kyakumoto, S., Han, Z, Silverman, S, Rosenfeld, M G, and Glass, C. K (1993) Differential orientations of the DNA-binding domain and carboxy-terminal dimerization interface regulate binding site selection by nuclear receptor heterodimers Genes Dev 7,1423-1435... 

Another example is a recently discovered second mode of action by which nuclear receptors modulate transcription. In contrast to DNA-binding-dependent mechanisms, cross talk refers here to gene regulation by protein-protein-interaction of nuclear receptors with other transcription factors, such as AP-1 or NF-kB. Consequently, the nuclear receptor acts as a corepressor or coactivator of transcription. 

Akiyama TE, Gonzalez FJ (2003) Regulation of P450 genes by liver-enriched transcription factors and nuclear receptors. Biochim Biophys Acta 1619 223-234... 

A nuclear receptor that is a key transcription factor in adipocytes. It plays a critical role in the control of adipocyte differentiation and is involved in the regulation of the expression of specific adipokines, including leptin and adiponectin. It has anti-inflammatory actions and is the target of the thiazolidinedione drugs. The preintegration complex is a complex of retroviral DNA and proteins that translocates from the cytosol into the nucleus prior to integration. Gene Therapy... 

A comparison of several different steroid receptors with thyroid hormone receptors revealed a remarkable conservation of the amino acid sequence in certain regions, particularly in the DNA-binding domains. This led to the realization that receptors of the steroid or thyroid type are members of a large superfamily of nuclear receptors. Many related members of this family have no known ligand at present and thus are called orphan receptors. The nuclear receptor superfamily plays a critical role in the regulation of gene transcription by hormones, as described in Chapter 43. 

As illustrated in Table 43-5, the discovery of the nuclear receptor superfamily has led to an important understanding of how a variety of metabolites and xenobi-otics regulate gene expression and thus the metabolism, detoxification, and elimination of normal body products and exogenous agents such as pharmaceuticals. Not surprisingly, this area is a fertile field for investigation of new therapeutic interventions. 

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