title: An Ideal PPAR Response Element Bound to and Activated by PPARα.
abstract: Peroxisome proliferator-activated receptor-α (PPARα), a nuclear receptor, plays an important role in the transcription of genes involved in fatty acid metabolism through heterodimerization with the retinoid x receptor (RXR). The consensus sequence of the PPAR response element (PPRE) is composed of two AGGTCA-like sequences directionally aligned with a single nucleotide spacer. PPARα and RXR bind to the 5' and 3' hexad sequences, respectively. However, the precise sequence definition of the PPRE remains obscure, and thus, the consensus sequence currently available remains AGGTCANAGGTCA with unknown redundancy. The vague PPRE sequence definition poses an obstacle to understanding how PPARα regulates fatty acid metabolism. Here we show that, rather than the generally accepted 6-bp sequence, PPARα actually recognized a 12-bp DNA sequence, of which the preferred binding sequence was WAWVTRGGBBAH. Additionally, the optimized RXRα hexad binding sequence was RGKTYA. Thus, the optimal PPARα/RXRα heterodimer binding sequence was WAWVTRGGBBAHRGKTYA. The single nucleotide substitution, which reduces binding of RXRα to DNA, attenuated PPARα-induced transcriptional activation, but this is not always true for PPARα. Using the definition of the PPRE sequence, novel PPREs were successfully identified. Taken altogether, the provided PPRE sequence definition contributes to the understanding of PPARα signaling by identifying PPARα direct target genes with functional PPARα response elements.
authors.affiliation: Department of Cell Biology and Molecular Medicine, Rutgers Biomedical Health Sciences, Newark, NJ 07103, United States of America.
authors.forename: John
authors.initials: J
authors.lastname: Tzeng
authors.affiliation: Department of Cell Biology and Molecular Medicine, Rutgers Biomedical Health Sciences, Newark, NJ 07103, United States of America.
authors.forename: Jaemin
authors.initials: J
authors.lastname: Byun
authors.affiliation: Department of Biochemistry and Molecular Biology, Rutgers Biomedical Health Sciences, Newark, NJ 07103, United States of America.
authors.forename: Ji Yeon
authors.initials: JY
authors.lastname: Park
authors.affiliation: Department of Cell Biology and Molecular Medicine, Rutgers Biomedical Health Sciences, Newark, NJ 07103, United States of America.
authors.forename: Takanobu
authors.initials: T
authors.lastname: Yamamoto
authors.affiliation: Department of Cell Biology and Molecular Medicine, Rutgers Biomedical Health Sciences, Newark, NJ 07103, United States of America.
authors.forename: Kevin
authors.initials: K
authors.lastname: Schesing
authors.affiliation: Department of Biochemistry and Molecular Biology, Rutgers Biomedical Health Sciences, Newark, NJ 07103, United States of America.
authors.forename: Bin
authors.initials: B
authors.lastname: Tian
authors.affiliation: Department of Cell Biology and Molecular Medicine, Rutgers Biomedical Health Sciences, Newark, NJ 07103, United States of America.
authors.forename: Junichi
authors.initials: J
authors.lastname: Sadoshima
authors.affiliation: Department of Cell Biology and Molecular Medicine, Rutgers Biomedical Health Sciences, Newark, NJ 07103, United States of America.
authors.forename: Shin-Ichi
authors.initials: S
authors.lastname: Oka
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D019556:COS Cells; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D016384:Consensus Sequence; D004247:DNA / Q000378:metabolism*; D019281:Dimerization; D005227:Fatty Acids / Q000378:metabolism; D017930:Genes, Reporter; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009154:Mutation; D032383:Myocytes, Cardiac / Q000378:metabolism; D047493:PPAR alpha / Q000172:deficiency / Q000378:metabolism*; D011485:Protein Binding; D051381:Rats; D020218:Response Elements; D047490:Retinoid X Receptor alpha / Q000378:metabolism*; D013047:Specific Pathogen-Free Organisms; D014158:Transcription, Genetic; D015533:Transcriptional Activation
chemical_list: D005227:Fatty Acids; D047493:PPAR alpha; D047490:Retinoid X Receptor alpha; D004247:DNA