Peroxisome proliferator response elements

The receptor protein (52 kDa) is a member of the steroid hormone receptor superfamily, which has a DNA-binding as well as ligand-binding domain. Another receptor, the retinoid X receptor is also involved, and after binding of the peroxisome proliferator, the two receptors form a heterodimer. This binds to a regulatory DNA sequence known as the peroxisome proliferator response element. The end result of the interaction between peroxisome proliferators and this system is that genes are switched on, leading to increases in synthesis (induction) of both microsomal and peroxisomal enzymes and possibly hyperplasia. 

Varanasi U, Chu R, Huang Q, et al. 1996. Identification of a peroxisome proliferator-responsive element upstream ofthe human peroxisomal fatty acyl coenzyme A oxidase gene. J Biol Chem271 2147-2155. 

Palmer, C.N., M.H. Hsu, A.S. Muerhoff, K.J. Griffin and E.F. Johnson. Interaction of the peroxisome proliferator-activated receptor alpha with the retinoid X receptor alpha unmasks a cryptic peroxisome proliferator response element that overlaps an ARP-1 binding site in the CYP4A6 promoter. J. Biol. Chem. 269 18083-18089, 1994. 

Fig. 2. Summary of the mode of action of peroxisome proliferators (PP) through the nuclear peroxisome proliferator-activated receptor (PPAR). The activation of PPAR requires the retinoic X receptor (RXR). The receptors are found in the cytoplasm and once the ligands bind (1) they undergo a conformational change (2) that allows the complex to enter the nucleus (3). The complex then binds to the peroxisome proliferator response element (PPRE) in the promoter region of target genes to alter transcription (4). Modified from Gervois et alP...

Fig. 6. Coordinated transcriptional regulation of fatty acid desaturases and elongases in mammals. PUFA, polyunsaturated fatty acids +, stimulation inhibition LXR, liver X receptor RXR retinoid X receptor SREBP, sterol regulatory element binding protein ChREBP, carbohydrate response element binding protein Mix, Max-like receptor PPAR-ot, peroxisome proliferator activated receptor alpha LXRE, liver X receptor response element SRE, sterol response element ChoRE, carbohydrate response element PPRE, peroxisome proliferator response element. (See color plate section, plate no. 6.)...

R. A. Rachubinski, and J.P. Capone (1993). Diverse peroxisome proliferator-activated receptors bind to the peroxisome proliferator-responsive elements of the rat hydratase/dehydrogenase and fatty acyl-CoA oxidase genes but differentially induce expression. Proc. Natl. Acad. Sci. USA 90, 5723-5727. 

W. Wahli, C.A. Meier et al. (1997). DNA binding properties of peroxisome proliferator-activated receptor subtypes on various natural peroxisome proliferator response elements. Importance of the 5 -flanking region. J. Biol. Chem. 272, 25252-25259. 

The abbreviations used are HMG-CoA, 3-hydroxy-3-melhylglutaryl-CoA CAT, chloramphenicol acetyltransferase PPAR, peroxisome proliferator-activated receptor PPRE, peroxisome proliferator-responsive element NRRE, nuclear receptor responsive element RXR, retinoid X receptor hRXRa, human 9-cis-retinoic acid receptor a mPPARa, mouse peroxisome proliferator-activated receptor a COUP-TP, chicken ovalbumin upstream-promoter transcription factor, HNF-4, hepatocyte nuclear factor 4 EMSA, electrophoretic mobility shift analysis tk, thymidine kinase NEFA, nonesterified fatty acids... 

Approximately 2.4kb of the promoter region of CTE-I and 2.8kb of the promoter region of MTE-I were sequenced in the 5 direction from the ATG start site. The promoter sequences were analysed for the presence of various transcription factor sites, using TESS String Based Search, which identified putative peroxisome proliferator response elements (PPREs) in both promoters. These regions of the promoters have now been cloned into a luciferase expression vector, to be used in transfection e5q)eriments to examine for functional PPREs. 

Zhang, B., Marcus, S.L., Sajjadi, F.G., Alvares, K., Reddy, J.K., Subramani, S., Rachubinski, R.A. Capone, J.R (1992). Proc. Nad Acad. Sci. U.S.A. 7541-7545. Identification of a peroxisome proliferator-responsive element upstream of the gene encoding rat peroxisomal enoyl-CoA hydratase/3-hydroxyacyl-CoA dehydrogenase. 

In rat liver at least 3 genes encode for peroxisomal thiolase of which thiolase B is inducible by peroxisome proliferators. To elueidate the meehanism of induction of thiolase B, an upstream 2.8kb fragment eontaining the promoter element has been sub-cloned and partially sequenced. The sequence analysis reavealed a putative PPRE (Peroxisome Proliferator Response Element) AGACCT T TGAACC at -681 to -668. ... 

Figure 17.2.2. PPARa mediates the rodent response to PPs. Binding sites for PPARa have been found in the promoters of genes associated with peroxisome proliferation such as acyl CoA oxidase, providing proof that PPARa can operate the switch and turn on expression of rodent genes known to be responsive. The binding site within the gene promoter is called a peroxisome proliferator response element (PPREs) and is defined by the DNA sequence TGACCT repeated once with a one letter spacer to give TGACCT n TGACCT.

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