Interaction of the peroxisome-proliferator-activated receptor and retinoid X receptor.

Gearing, Katharine L.; Göttlicher, Martin; Teboul, Michèle; Widmark, E; Gustafsson, Jan‐Åke

doi:10.1073/pnas.90.4.1440

Cited by 354 publications

(219 citation statements)

References 28 publications

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“…31 When activated, PPARs form heterodimers with the retinoid X receptor (RXR) and bind to peroxisome proliferator response elements (PPREs), which are very similar in sequence to EREs and other hormone response elements. 32 It was previously reported that PA derivatives can activate human PPARs with a relative potency that correlated with their ability to induce cytostasis in human tumor cells. 29,33 In addition to binding and activating PPREs, Keller et al 30 provided evidence that the activated PPAR/ RXR heterodimers are able to also bind some ERE sequences (including ERE v ), but do not activate gene transcription.…”

Section: Discussionmentioning

confidence: 98%

Inhibition of estrogen-dependent breast cell responses with phenylacetate

et al. 2001

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The aromatic fatty acid phenylacetate (PA) and its analogs have come under intense investigation due to their ability to cause the growth arrest of a variety of neoplasia, including human breast cancer. We have determined that PA and its halide derivative 4-chlorophenylacetate (4-CPA) showed marked antiproliferative activity on 3 of 6 human breast cancer cell lines tested. Interestingly, the 3 cell lines that were growth inhibited by PA and 4-CPA were estrogen receptor (ER) positive (T47-D, MCF-7 and ZR-75-1) whereas those that were little affected by these compounds were ER-negative (MDA-MB-157, MDA-MB-231 and SK-Br-3). Dose response studies indicated that 4-CPA inhibited the growth of the sensitive (ER؉) cell lines with a potency 3-4 times that of PA. These findings suggest that there is "crosstalk" between the PA and estrogen signaling pathways such that PA can directly inhibit estrogen-dependent events. This hypothesis was directly tested in vitro using ER؉ MCF-7 cells that were stably transfected with a luciferase reporter construct driven by the full length ( Key words: phenylacetate; breast cancer; estrogen; receptorBreast cancer is 1 of the most prevalent types of cancer observed in women, developing in approximately 1 of 9 women sometime during their lifetime. The etiology of this malignancy is known to involve a complex interplay of genetic, environmental, and hormonal factors that influence the physiological status of the host. 1,2 With regards to the latter factor, there is considerable data that implicate the involvement of steroid hormones, especially estrogen, in the development and progression of breast cancer. This fact has lead to the use of antiestrogens in the therapeutic intervention of this disease. To date, the clinical use of antiestrogens has been limited to compounds that inhibit estrogen signaling at the level of the estrogen receptor (ER) by competing with the ligand (i.e., estrogen) for receptor binding. 3 Although shown to be extremely useful, the clinical results are often unpredictable due to the complex functional activity of ERs liganded with different antiestrogen compounds or the ability of the receptors to undergo changes (mutations or otherwise) that can alter their functional characteristics or response to estrogen antagonists. 4 Thus, there is a need to develop therapeutic compounds that can inhibit the estrogen signaling pathway by mechanisms that may not depend upon competitive ligand binding to the ER.Aromatic fatty acids, of which phenylacetate (PA) is a prototype, constitute a new class of low toxicity drugs with demonstrated antitumor activity in experimental models and in humans. PA is a natural metabolite of phenylalanine that was originally described as a plant growth hormone. 5 Normally found in micromolar concentrations in human plasma, PA has a long clinical history as treatment for conditions associated with hyperammonemia such as in children with urea cycle disorders. 6,7 This clinical experience has indicated that millimolar blood serum levels can be achiev...

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Section: Discussionmentioning

confidence: 98%

Inhibition of estrogen-dependent breast cell responses with phenylacetate

et al. 2001

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“…As additive or synergistic effects on glucose, lipid metabolism and gene activation have been described for RXR and PPAR␥ ligands (67)(68)(69)(70)(71)(72)(73), experiments of coincubation of 9cRA with ROSI were performed (Fig. 4).…”

Section: Discussionmentioning

confidence: 99%

9-cis-Retinoic Acid (9cRA), a Retinoid X Receptor (RXR) Ligand, Exerts Immunosuppressive Effects on Dendritic Cells by RXR-Dependent Activation: Inhibition of Peroxisome Proliferator-Activated Receptor γ Blocks Some of the 9cRA Activities, and Precludes Them to Mature Phenotype Development

Zapata-Gonzalez

Rueda

Pétriz

et al. 2007

The Journal of Immunology

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At nanomolar range, 9-cis-retinoic acid (9cRA) was able to interfere in the normal differentiation process from human monocyte to immature dendritic cell (DC) and produced a switch in mature DCs to a less stimulatory mode than untreated cells. 9cRA-treated mature DCs secreted high levels of IL-10 with an IL-12 reduced production. The phenotypic alterations unleashed by 9cRA were similar but not identical to other specific retinoid X receptor (RXR) agonists and to those already reported for rosiglitazone, a PPARγ activator, on DCs. The simultaneous addition of 9cRA and rosiglitazone on DCs displayed additive effects. Moreover, addition to cultures of GW9662, a specific inhibitor of PPARγ, or the RXR pan-antagonist HX603, blocked these changes. All these results suggest an activation of PPARγ-RXR and other RXR containing dimers by 9cRA in DCs. Finally, both GW9662 and HX603 by themselves altered the maturation process unleashed by TNFα, poly(I:C) or LPS on human DCs further suggesting that the heterodimer PPARγ-RXR must fulfill a significant role in the physiological maturation process of these cells in addition to the repressing effects reported till now for this nuclear receptor.

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“…and organ-specific with the strongest effects exerted in the liver of rat (see, for example, [41). In addition to increasing peroxisome number and increased transcription of certain peroxisomal j3-oxidation enzymes [5], several other lipid-metabolising enzymes are induced not only in peroxisomes, but also in mitochondria, endoplasmic reticulum and cytosol .…”

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confidence: 99%

Peroxisome Proliferators Differentially Regulate Long‐chain Acyl‐CoA Thioesterases in Rat Liver

Svensson

Wilcke

Alexson

1995

European Journal of Biochemistry

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We have investigated the effects of peroxisome proliferators on rat liver long-chain acyl-CoA thioesterase activities. Subcellular fractionations of liver homogenates from control, clofibrate-and di(2-ethylhexy1)phthalate-treated rats confirmed earlier studies which demonstrated that peroxisome-proliferating drugs induce long-chain acyl-CoA thioesterase activity mainly in the mitochondrial and cytosolic fractions. The aim of the present study was to investigate whether the induced activities were due to increases in normally expressed enzymes, or due to induction of novel enzymes. To investigate whether structurally different peroxisome proliferators differentially induced thioesterase activities, we tested the effects of di(2-ethy1hexyl)phthalate (a plastisizer) and the hypolipidemic drug clofibrate. For this purpose, we established an analytical size exclusion chromatography method. Chromatography of solubilised mitochondrial matrix proteins showed that the activity in control mitochondria was mainly due to enzymes with molecular masses of about 50 kDa and 35 kDa. The activity in samples prepared from clofibrate-and di(2-ethylhexy1)phthalate-treated rats eluted as proteins of about 40 kDa and 110 kDa. Highly purified peroxisomes contained two peaks of activity, which were not induced, that corresponded to molecular masses of 40 kDa and 80 kDa. The 80-kDa peak was shown to be due to dimerization by addition of glycerol. Chromatography of cytosolic fractions from control rat livers indicated the presence of long-chain acylCoA thioesterases with molecular masses of approximately 35 kDa and 125 kDa and a broad peak corresponding to a high-molecular-mass protein. The activity in cytosolic fractions from peroxisome-proliferator-treated rats eluted mainly as peaks corresponding to 40, 110 and 150 kDa. In addition, in the 110-kDa peak, a different degree of induction and different chain-length specificities were caused by clofibrate and di(2-ethylhexyl)phthalate, suggesting that these peroxisome proliferators differentially regulate the cytosolic acyl-CoA thioesterase activities. Western blot analysis showed that enzymes in the 40-kDa peak of the peroxisomal and cytosolic fractions were structurally related, but not identical, to a 40-kDa mitochondrial very-long-chain acyl-CoA thioesterase.Our data show that the increased acyl-CoA thioesterase activities in mitochondria and cytosol were mainly due to induction of acyl-CoA thioesterases which are not, or only weakly, expressed under normal conditions. Keywords. Acyl-CoA thioesterases ; peroxisome proliferators ; differential induction.Several compounds have been shown to lower plasma lipids in rodents and humans. The fibrate class of hypolipidemic drugs, which was discovered about 30 years ago, proved efficient in lowering triacylglycerols. However, these drugs appear to be hepatocarcinogens when tested in rodents [I, 21. An early observation was the pronounced proliferation of peroxisomes in the liver of rats treated with, for example, clofibrate Abbreviations. Pht(H...

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Interaction of the peroxisome-proliferator-activated receptor and retinoid X receptor.

Cited by 354 publications

References 28 publications

Inhibition of estrogen-dependent breast cell responses with phenylacetate

Inhibition of estrogen-dependent breast cell responses with phenylacetate

9-cis-Retinoic Acid (9cRA), a Retinoid X Receptor (RXR) Ligand, Exerts Immunosuppressive Effects on Dendritic Cells by RXR-Dependent Activation: Inhibition of Peroxisome Proliferator-Activated Receptor γ Blocks Some of the 9cRA Activities, and Precludes Them to Mature Phenotype Development

Peroxisome Proliferators Differentially Regulate Long‐chain Acyl‐CoA Thioesterases in Rat Liver

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