Dataset Information

ISL1 regulates peroxisome proliferator-activated receptor ? activation and early adipogenesis via bone morphogenetic protein 4-dependent and -independent mechanisms.

ABSTRACT: While adipogenesis is controlled by a cascade of transcription factors, the global gene expression profiles in the early phase of adipogenesis are not well defined. Using microarray analysis of gene expression in 3T3-L1 cells, we have identified evidence for the activity of 2,568 genes during the early phase of adipocyte differentiation. One of these, the ISL1 gene, was of interest since its expression was markedly upregulated 1 h after initiation of differentiation, with a subsequent rapid decline. Overexpression of ISL1 at early times during adipocyte differentiation but not at later times was found to profoundly inhibit differentiation. This was accompanied by moderate downregulation of peroxisome proliferator-activated receptor ? (PPAR?) levels, substantial downregulation of PPAR? downstream genes, and downregulation of bone morphogenetic protein 4 (BMP4) levels in preadipocytes. Readdition of BMP4 overcame the inhibitory effect of ISL1 on the expression of PPAR? but not aP2, a gene downstream of PPAR?, and BMP4 also partially rescued ISL1 inhibition of adipogenesis, an effect which is additive with rosiglitazone. These results suggest that ISL1 is intimately involved in early regulation of adipogenesis, modulating PPAR? expression and activity via BMP4-dependent and -independent mechanisms. Our time course gene expression survey sets the stage for further studies to explore other early and immediate regulators.

SUBMITTER: Ma X

PROVIDER: S-EPMC4187726 | biostudies-literature | 2014 Oct

REPOSITORIES: biostudies-literature

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ISL1 regulates peroxisome proliferator-activated receptor γ activation and early adipogenesis via bone morphogenetic protein 4-dependent and -independent mechanisms.

Ma Xiuquan X Yang Pengyi P Kaplan Warren H WH Lee Bon Hyang BH Wu Lindsay E LE Yang Jean Yee-Hwa JY Yasunaga Mayu M Sato Kenzo K Chisholm Donald J DJ James David E DE

Molecular and cellular biology 20140721 19

While adipogenesis is controlled by a cascade of transcription factors, the global gene expression profiles in the early phase of adipogenesis are not well defined. Using microarray analysis of gene expression in 3T3-L1 cells, we have identified evidence for the activity of 2,568 genes during the early phase of adipocyte differentiation. One of these, the ISL1 gene, was of interest since its expression was markedly upregulated 1 h after initiation of differentiation, with a subsequent rapid decl ...[more]

PMID: 25047837

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Project description:BackgroundProstate cancer (PC) remains a leading cause of cancer mortality and the most successful chemopreventative and treatment strategies for PC come from targeting the androgen receptor (AR). Although AR plays a key role, it is likely that other molecular pathways also contribute to PC, making it essential to identify and develop drugs against novel targets. Recent studies have identified peroxisome proliferator-activated receptor gamma (PPARγ), a nuclear receptor that regulates fatty acid (FA) metabolism, as a novel target in PC, and suggest that inhibitors of PPARγ could be used to treat existing disease. We hypothesized that PPARγ acts through AR-dependent and independent mechanisms to control PC development and growth and that PPARγ inhibition is a viable PC treatment strategy.MethodsImmunohistochemistry was used to determine expression of PPARү in a cohort of patients with PC. Standard molecular techniques were used to investigate the PPARү signaling in PC cells as well a xenograft mouse model to test PPARү inhibition in vivo. Kaplan-Meier curves were created using cBioportal.ResultsWe confirmed the expression of PPARү in human PC. We then showed that small molecule inhibition of PPARγ decreases the growth of AR-positive and -negative PC cells in vitro and that T0070907, a potent PPARγ antagonist, significantly decreased the growth of human PC xenografts in nude mice. We found that PPARγ antagonists or small interfering RNA (siRNA) do not affect mitochondrial activity nor do they cause apoptosis; instead, they arrest the cell cycle. In AR-positive PC cells, antagonists and siRNAs reduce AR transcript and protein levels, which could contribute to growth inhibition. AR-independent effects on growth appear to be mediated by effects on FA metabolism as the specific FASN inhibitor, Fasnall, inhibited PC cell growth but did not have an additive effect when combined with PPARγ antagonists. Patients with increased PPARү target gene expression, but not alterations in PPARү itself, were found to have significantly worse overall survival.ConclusionsHaving elucidated the direct cancer cell effects of PPARγ inhibition, our studies have helped to determine the role of PPARγ in PC growth, and support the hypothesis that PPARγ inhibition is an effective strategy for PC treatment.

Dataset Information

ISL1 regulates peroxisome proliferator-activated receptor ? activation and early adipogenesis via bone morphogenetic protein 4-dependent and -independent mechanisms.

Publications

ISL1 regulates peroxisome proliferator-activated receptor γ activation and early adipogenesis via bone morphogenetic protein 4-dependent and -independent mechanisms.

Similar Datasets

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