Miyata K S, Zhang B, Marcus S L, Capone J P, Rachubinski R A
Department of Biochemistry, McMaster University, Hamilton, Ontario, Canada.
J Biol Chem. 1993 Sep 15;268(26):19169-72.
Peroxisome proliferators form a family of diverse xenobiotic compounds that includes hypolipidemic agents, herbicides, and plasticizers. These compounds activate transcription of a subset of nuclear genes including those encoding peroxisomal fatty acid beta-oxidation enzymes, whose elevated activities can lead to hepatocarcinogenesis. Induction of the genes encoding fatty acyl-CoA oxidase and hydratase-dehydrogenase, the first and second enzymes of the pathway, is mediated by peroxisome proliferator-activated nuclear receptors (PPARs) that bind to upstream responsive elements (PPREs) through heterodimerization with retinoid X receptors. We demonstrate that the chicken ovalbumin upstream promoter transcription factor 1 (COUP-TF1), another member of the nuclear hormone receptor superfamily, binds to the hydratase-dehydrogenase PPRE in vitro and in vivo and antagonizes PPAR-dependent signaling. These data suggest that members of the COUP-TF family play a role in modulating receptor-mediated activation of peroxisome proliferator-responsive genes.
过氧化物酶体增殖剂构成了一类多样的外源性化合物家族，其中包括降血脂药物、除草剂和增塑剂。这些化合物可激活一部分核基因的转录，包括那些编码过氧化物酶体脂肪酸β-氧化酶的基因，这些酶活性的升高会导致肝癌发生。该途径的第一种和第二种酶，即脂肪酸酰基辅酶A氧化酶和水化酶-脱氢酶的基因诱导，是由过氧化物酶体增殖剂激活的核受体（PPARs）介导的，PPARs通过与视黄酸X受体异二聚化而与上游反应元件（PPREs）结合。我们证明，核激素受体超家族的另一个成员——鸡卵清蛋白上游启动子转录因子1（COUP-TF1），在体外和体内均能与水化酶-脱氢酶PPRE结合，并拮抗PPAR依赖性信号传导。这些数据表明，COUP-TF家族成员在调节受体介导的过氧化物酶体增殖剂反应性基因激活中发挥作用。
