PPARγ, 10 years later

Lazar, Mitchell A.

doi:10.1016/j.biochi.2004.10.021

Cited by 132 publications

(96 citation statements)

References 63 publications

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“…In a sense, the genomic ontology analysis served as a "reality check" on the data set, and the fact that the most significant cohorts of target genes segregate into ontological classes associated with metabolism, proliferation, and motility is reassuring in light of the cellular phenotype that attends PPAR␥ activation, published data on metabolic effects of PPAR␥ in other cell types (103)(104)(105), and our analysis of PPAR␥ effects in nontransformed gastrointestinal epithelial cells (14). However, genomic ontology inferred an entirely unanticipated connection between PPAR␥ and calcium signaling.…”

Section: Discussionmentioning

confidence: 99%

Functional Genomic Analysis Reveals Cross-talk between Peroxisome Proliferator-activated Receptor γ and Calcium Signaling in Human Colorectal Cancer Cells

Bush

Havens

Necela

et al. 2007

Journal of Biological Chemistry

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Activation of PPAR␥ in MOSER cells inhibits anchoragedependent and anchorage-independent growth and invasion through Matrigel-coated transwell membranes. We carried out a longitudinal two-class microarray analysis in which mRNA abundance was measured as a function of time in cells treated with a thiazolidinedione PPAR␥ agonist or vehicle. A statistical machine learning algorithm that employs an empirical Bayesian implementation of the multivariate HotellingT2 score was used to identify differentially regulated genes. HotellingT2 scores, MB statistics, and maximum median differences were used as figures of merit to interrogate genomic ontology of these targets. Three major cohorts of genes were regulated: those involved in metabolism, DNA replication, and migration/motility, reflecting the cellular phenotype that attends activation of PPAR␥. The bioinformatic analysis also inferred that PPAR␥ regulates calcium signaling. This response was unanticipated, because calcium signaling has not previously been associated with PPAR␥ activation. Ingenuity pathway analysis inferred that the nodal point in this cross-talk was Down syndrome critical region 1 (DSCR1). DSCR1 is an endogenous calcineurin inhibitor that blocks dephosphorylation and activation of members of the cytoplasmic component of nuclear factor of activated T cells transcription factors. Lentiviral short hairpin RNA-mediated knockdown of DSCR1 blocks PPAR␥ inhibition of proliferation and invasion, indicating that DSCR1 is required for suppression of transformed properties of early stage colorectal cancer cells by PPAR␥. These data reveal a novel, heretofore unappreciated link between PPAR␥ and calcium signaling and indicate that DSCR1, which has previously been thought to function by suppression of the angiogenic response in endothelial cells, may also play a direct role in transformation of epithelial cells.

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Section: Discussionmentioning

confidence: 99%

Functional Genomic Analysis Reveals Cross-talk between Peroxisome Proliferator-activated Receptor γ and Calcium Signaling in Human Colorectal Cancer Cells

Bush

Havens

Necela

et al. 2007

Journal of Biological Chemistry

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“…It is only more recently that TZDs were described as selective ligands for the receptor, bridging the gap between PPARg and insulin sensitivity ( Figure 5) [205,206].…”

Section: Pparg As a Therapeutic Target In Fat Related Diseasesmentioning

confidence: 99%

Fat poetry: a kingdom for PPARγ

2007

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Adipose tissue is not an inert cell mass contributing only to the storage of fat, but a sophisticated ensemble of cellular components with highly specialized and complex functions. In addition to managing the most important energy reserve of the body, it secretes a multitude of soluble proteins called adipokines, which have beneficial or, alternatively, deleterious effects on the homeostasis of the whole body. The expression of these adipokines is an integrated response to various signals received from many organs, which depends heavily on the integrity and physiological status of the adipose tissue. One of the main regulators of gene expression in fat is the transcription factor peroxisome proliferatoractivated receptor g (PPARg), which is a fatty acid-and eicosanoid-dependent nuclear receptor that plays key roles in the development and maintenance of the adipose tissue. Furthermore, synthetic PPARg agonists are therapeutic agents used in the treatment of type 2 diabetes.This review discusses recent knowledge on the link between fat physiology and metabolic diseases, and the roles of PPARg in this interplay via the regulation of lipid and glucose metabolism. Finally, we assess the putative benefits of targeting this nuclear receptor with still-to-be-identified highly selective PPARg modulators.

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“…After establishing the capability of PELP1 to bind and function as a coactivator of RXR␣, we next tested the possibility of whether PELP1 also modulates transcription function of a RXR␣ heterodimer. A large body of the previous work suggests that RXR␣-PPAR␥ remains the best-studied heterodimer in terms of activating ligands, participating response elements, and the resulting physiological effects (26). The RXR␣-PPAR␥ heterodimer specifically binds to the PPRE sequence motifs and brings about transcription in response to both PPAR␥ and RXR␣ ligands.…”

Section: Pelp1 Promotes Ppar Response Element-driven Transcription-rxr␣mentioning

confidence: 99%

9-cis-Retinoic Acid Up-regulates Expression of Transcriptional Coregulator PELP1, a Novel Coactivator of the Retinoid X Receptor α Pathway

Singh

Gururaj

Vadlamudi

et al. 2006

Journal of Biological Chemistry

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Retinoid X receptor ␣ (RXR␣), functioning as either a homodimer or a heterodimer with peroxisome proliferator receptors, is known to be involved in manifesting antiproliferative effects in cells. Consequently, studies of RXR␣ functions and its coregulators have been in the focus for therapeutic approaches against cancer. Here we have discovered that 9-cis-retinoic acid (9-cis-RA), a RXR␣-specific ligand, upregulated the expression of transcriptional coregulatory protein PELP1 (proline-, glutamic acid-, and leucine-rich protein 1). PELP1 functioned as a coactivator of RXR␣, increasing its transactivation function in response to 9-cis-RA as evident by the retinoid X receptor response element-luciferase assays. PELP1 was found to be a binding partner of RXR␣, and the binding interactions were confirmed both in vitro and in vivo. An electrophoretic mobility shift assay showed greater formation and stability of RXR␣ homodimers on consensus oligonucleotides in PELP1-overexpressing clones in comparison to the pcDNA clones. The presence of PELP1 in these oligonucleotide-bound RXR␣ homodimers was proved by the supershift of the complex when incubated with PELP1-specific antibody. PELP1-overexpressing stable MCF-7 cells exhibited a significantly higher extent of 9-cis-RA-induced apoptosis than the control pcDNA clones. Silencing of PELP1 expression in parental MCF-7 cells and PELP1-overexpressing clones using PELP1-specific RNA-mediated interference compromised the susceptibility to 9-cis-RA-induced apoptosis. PELP1 could also function as a coactivator of the RXR␣-peroxisome proliferator-activated receptor (PPAR␥) heterodimer as evident by the peroxisome proliferator-activated receptor response element-luciferase assay in response to both 9-cis-RA and PPAR␥-specific ligands. This was reinforced by the higher propensity of PELP1-overexpressing clones to undergo differentiation in response to PPAR␥-specific ligands. This study has revealed a novel facet of PELP1 functions and identified it to be an important potentiator of the antiproliferative effects of 9-cis-RA and PPAR␥-specific ligands. Nuclear receptors (NR)2 are ligand-activated transcription factors that on binding to small lipophilic signal molecules facilitate gene transcription and regulate diverse vital biological processes such as cell survival, proliferation, differentiation, and apoptosis (1). On activation, the NR in their homodimeric or heterodimeric complexes with other NR bind to specific DNA sequences referred to as "response elements," which are present in the regulatory elements of target genes. On DNA binding, the NR orchestrate gene transcription by interacting with the basal transcriptional machinery through bridging factors, referred to broadly as coactivator proteins. One of the potential functions of the coactivator proteins is to directly or indirectly remodel the local chromatin structure through covalent modification of histones (acetylation, phosphorylation, or methylation) resulting in opening of chromatin, greater accessibility of the targe...

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PPARγ, 10 years later

Cited by 132 publications

References 63 publications

Functional Genomic Analysis Reveals Cross-talk between Peroxisome Proliferator-activated Receptor γ and Calcium Signaling in Human Colorectal Cancer Cells

Functional Genomic Analysis Reveals Cross-talk between Peroxisome Proliferator-activated Receptor γ and Calcium Signaling in Human Colorectal Cancer Cells

Fat poetry: a kingdom for PPARγ

9-cis-Retinoic Acid Up-regulates Expression of Transcriptional Coregulator PELP1, a Novel Coactivator of the Retinoid X Receptor α Pathway

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