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An Ideal PPAR Response Element Bound to and Activated by PPAR?.

ABSTRACT: Peroxisome proliferator-activated receptor-? (PPAR?), 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. PPAR? 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 PPAR? regulates fatty acid metabolism. Here we show that, rather than the generally accepted 6-bp sequence, PPAR? actually recognized a 12-bp DNA sequence, of which the preferred binding sequence was WAWVTRGGBBAH. Additionally, the optimized RXR? hexad binding sequence was RGKTYA. Thus, the optimal PPAR?/RXR? heterodimer binding sequence was WAWVTRGGBBAHRGKTYA. The single nucleotide substitution, which reduces binding of RXR? to DNA, attenuated PPAR?-induced transcriptional activation, but this is not always true for PPAR?. Using the definition of the PPRE sequence, novel PPREs were successfully identified. Taken altogether, the provided PPRE sequence definition contributes to the understanding of PPAR? signaling by identifying PPAR? direct target genes with functional PPAR? response elements.

SUBMITTER: Tzeng J

PROVIDER: S-EPMC4524655 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

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An Ideal PPAR Response Element Bound to and Activated by PPARα.

Tzeng John J Byun Jaemin J Park Ji Yeon JY Yamamoto Takanobu T Schesing Kevin K Tian Bin B Sadoshima Junichi J Oka Shin-Ichi S

PloS one 20150804 8

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 ...[more]

PMID: 26241474

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Project description:Stromal Derived Factor-1? (SDF-1?) and its cognate receptor CXCR4 play a key role in mediating breast cancer cell invasion and metastasis. Therefore, drugs able to inhibit CXCR4 activation may add critical tools to reduce tumor progression, especially in the most aggressive form of the breast cancer disease. Peroxisome Proliferator-Activated Receptor (PPAR) ?, a member of the nuclear receptor superfamily, has been found to downregulate CXCR4 gene expression in different cancer cells, however the molecular mechanism underlying this effect is not fully understood. Here, we identified a novel PPAR?-mediated mechanism that negatively regulates CXCR4 expression in both epithelial and stromal breast cancer cells. We found that ligand-activated PPAR? downregulated CXCR4 transcriptional activity through the recruitment of the silencing mediator of retinoid and thyroid hormone receptor (SMRT) corepressor onto a newly identified PPAR response element (PPRE) within the CXCR4 promoter in breast cancer cell lines. As a consequence, the PPAR? agonist rosiglitazone (BRL) significantly inhibited cell migration and invasion and this effect was PPAR?-mediated, since it was reversed in the presence of the PPAR? antagonist GW9662. According to the ability of cancer-associated fibroblasts (CAFs), the most abundant component of breast cancer stroma, to secrete high levels of SDF-1?, BRL reduced migratory promoting activities induced by conditioned media (CM) derived from CAFs and affected CXCR4 downstream signaling pathways activated by CAF-CM. In addition, CAFs exposed to BRL showed a decreased expression of CXCR4, a reduced motility and invasion along with a phenotype characterized by an altered morphology. Collectively, our findings provide novel insights into the role of PPAR? in inhibiting breast cancer progression and further highlight the utility of PPAR? ligands for future therapies aimed at targeting both cancer and surrounding stromal cells in breast cancer patients.

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An Ideal PPAR Response Element Bound to and Activated by PPAR?.

Publications

An Ideal PPAR Response Element Bound to and Activated by PPARα.

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