T0070907, a Selective Ligand for Peroxisome Proliferator-activated Receptor γ, Functions as an Antagonist of Biochemical and Cellular Activities

Lee, Gary; Elwood, Fabienne; McNally, John; Weiszmann, Jennifer; Lindström, Michelle; Amaral, Kate; Nakamura, Motonao; Miao, Shichang; Cao, Ping; Learned, R. Marc; Chen, Jinlong; Li, Yang

doi:10.1074/jbc.m200743200

Cited by 276 publications

(240 citation statements)

References 33 publications

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“…40 Various long-chain fatty acids 20 and chemical compounds 23 can bind to and activate PPARG, leading to changes in mRNA expression of target genes. 26 Besides PPARG, LXRA and SREBF1 are 2 key transcription factors also involved in lipid metabolism. 1 Therefore, the data demonstrating that miR-26a/b overexpression altered PPARG, SREBF1 and LXRA expression profiles and the data showing that cells treated with Ad-PPARG/Ad-SREBF1 and T09 (the agonist of LXRA) up-regulated expression of miR-26 and CTDSP family expression seem to confirm a functional role among the transcription regulators and miR26a/b.…”

Section: Discussionmentioning

confidence: 99%

MicroRNA-26a/b and their host genes synergistically regulate triacylglycerol synthesis by targeting theINSIG1gene

et al. 2016

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The microRNA-26 (miR-26) family is known to control adipogenesis in non-ruminants. The genomic loci of miR-26a and miR-26b have been localized in the introns of genes encoding for the proteins of the Cterminal domain RNA polymerase II polypeptide A small phosphatase (CTDSP) family. Insulin-induced gene 1 (INSIG1) encodes a protein with a key role in the regulation of lipogenesis in rodent liver. In the present study, we investigated the synergistic function of the miR-26 family and their host genes in goat mammary epithelial cells (GMEC). Downregulation of miR-26a/b and their host genes in GMEC decreased the expression of genes relate to fatty acid synthesis (PPARG, LXRA, SREBF1, FASN, ACACA, GPAM, LPIN1, DGAT1 and SCD1), triacylglycerol accumulation and unsaturated fatty acid synthesis. Luciferase reporter assays confirmed INSIG1 as a direct target of miR-26a/b. Furthermore, inhibition of the CTDSP family also downregulated the expression of INSIG1. Taken together, our findings highlight a functional association of miR-26a/b, their host genes and INSIG1, and provide new insights into the regulatory network controlling milk fat synthesis in GMEC. The data indicate that targeting this network via nutrition might be important for regulating milk fat synthesis in ruminants.

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Section: Discussionmentioning

confidence: 99%

MicroRNA-26a/b and their host genes synergistically regulate triacylglycerol synthesis by targeting theINSIG1gene

et al. 2016

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“…The PPARg antagonists GW9662 and T0070907 irreversibly modify Cys 285 in the PPARg ligand -binding site via a nucleophilic aromatic substitution of chlorine (26,27). The same cysteine residue is essential for the activity and covalent binding of some PPARg agonists such as 15d-PGJ2 but not for rosiglitazone (28).…”

Section: Fh535 Antagonizes Both Ppar; and Ppard Activitymentioning

confidence: 99%

A small-molecule inhibitor of Tcf/β-catenin signaling down-regulates PPARγ and PPARδ activities

Handeli

Simon

2008

Molecular Cancer Therapeutics

161

137

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Activation of the Wnt/B-catenin signaling pathway occurs in several types of cancers and thus it is an attractive target for anticancer drug development. To identify compounds that inhibit this pathway, we screened a chemical library using a cell-based B-catenin/Tcf -responsive reporter. We identified FH535, a compound that suppresses both Wnt/B-catenin and peroxisome proliferator -activated receptor (PPAR) signaling. FH535 antagonizes both PPAR; and PPARD ligand -dependent activation and shows structural similarity to GW9662, a known PPAR; antagonist. The effect of FH535 on B-catenin/Tcf activity is reduced in cells carrying a deletion of the PPARd gene, as well as by the PPAR; agonist lysophosphatidic acid. Mechanistically, FH535 inhibits recruitment of the coactivators B-catenin and GRIP1 but not the corepressors NCoR and SMRT. Its repression of B-catenin recruitment, in comparison with GW9662, is linked to FH535 ¶s unique capability to inhibit the Wnt/B-catenin signaling pathway. The antiproliferation effect of the compound observed on some transformed colon lung and liver cell lines is suggestive of its potential therapeutic value in the treatment of cancer. [Mol Cancer Ther 2008;7(3):521 -9]

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“…As curcumin-induced apoptosis has been linked to its activity as a PPARg receptor agonist, we examined whether TOO70907, a nonthiazolidinedione PPARg receptor antagonist, could inhibit curcumin-induced apoptosis in B-CLL cells [23]. Prior studies have reported an apparent TOO70907 binding affinity of 1 nM and demon- strated that this compound blocks both cell based reporter gene expression and adipocyte differentiation [23]. TOO70907 itself induced apoptosis in B-CLL cells at concentrations of 1 mM or higher (data not shown).…”

Section: Pparg Receptor and Nf-kb Studiesmentioning

confidence: 99%

Preclinical assessment of curcumin as a potential therapy for B‐CLL

et al. 2006

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Curcumin, the principle component of the spice turmeric, has been used as an anti-inflammatory medication in India and China for centuries. Recent studies, predominantly using actively dividing cell lines, have suggested that this compound could be used as a chemopreventative or therapeutic agent for epithelial tumors. As curcumin has been reported to inhibit the NIK/IKK complex, an activity that would be expected to induce apoptosis in B cell malignancies, we sought to determine whether curcumin induces apoptosis in vitro in primary chronic lymphocytic leukemia (B-CLL) cells. Primary leukemic cells were incubated with varying dosages of curcumin, followed by assessment for apoptosis. The role of PPARg or NF-kB signaling in curcumin-induced apoptosis was examined by cotreatment with a PPARg antagonist or EMSA of nuclear NFkB complexes. We also examined whether a clinically achievable concentration of curcumin (1 mM) would augment the apoptotic effects of fludarabine, dexamethasone, vincristine or the PDE4 inhibitor rolipram. In B-CLL cells from 14 patients, curcumin-induced apoptosis with a mean EC 50 of 5.5 mM. In contrast, the EC 50 for whole mononuclear cells from a healthy donor was 21.8 mM. In a 48 hr wash-out time course, curcumin-induced apoptosis was time-dependent, with a substantial reduction in apoptosis observed when curcumin was removed after 5 hr. Curcumin treatment reduced basal nuclear NF-kB levels and 1 mM curcumin augmented both vinca alkaloid and PDE4 inhibitor-induced apoptosis in B-CLL cells. Our studies suggest that curcumin may augment the efficacy of established or experimental therapies for B-CLL. Am. J. Hematol. 82:23-30, 2007. V V C 2006 Wiley-Liss, Inc.

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T0070907, a Selective Ligand for Peroxisome Proliferator-activated Receptor γ, Functions as an Antagonist of Biochemical and Cellular Activities

Cited by 276 publications

References 33 publications

MicroRNA-26a/b and their host genes synergistically regulate triacylglycerol synthesis by targeting theINSIG1gene

MicroRNA-26a/b and their host genes synergistically regulate triacylglycerol synthesis by targeting theINSIG1gene

A small-molecule inhibitor of Tcf/β-catenin signaling down-regulates PPARγ and PPARδ activities

Preclinical assessment of curcumin as a potential therapy for B‐CLL

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