Identification of a transcriptionally active peroxisome proliferator-activated receptor α-interacting cofactor complex in rat liver and characterization of PRIC285 as a coactivator
Identification of a transcriptionally active peroxisome proliferator-activated receptor α-interacting cofactor complex in rat liver and characterization of PRIC285 as a coactivator
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DOI：
10.1073/pnas.182426699
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发表时间：
2002-09-03
影响因子：
11.1
通讯作者：
Reddy, JK
中科院分区：
文献类型：
--
作者：
Surapureddi, S;Yu, ST;Reddy, JK
过氧化物酶体增殖物激活受体α（PPARalpha）在由结构多样的合成化学品（称为过氧化物酶体增殖物）诱导的细胞特异性多效性反应中起着核心作用。配体核受体的转录调控涉及形成多蛋白复合物的辅因子的参与，以实现细胞和基因特异性转录。在这里，我们报告的识别这样的转录活性PPARalpha相互作用辅因子（PRIC）复杂的大鼠肝细胞核提取物，与全长PPARalpha的环丙贝特，合成配体，和白三烯B4，天然配体的存在下相互作用。配体PPARalpha-PRIC复合物增强了从含有过氧化物酶体增殖物应答元件的过氧化物酶体烯酰辅酶A水合酶/L-3-羟酰辅酶A脱氢酶双功能酶基因启动子模板的转录。大鼠肝脏PRIC复合物包含约25个多肽，并通过质谱和有限序列分析确定它们的身份。这些肽中的18种含有一个或多个与核受体相互作用所必需的LXXLL基序。PRIC复合物包括已知的共激活物或共激活物结合蛋白（CBP、SRC-1 PBP、PRIP、PIMT、TRAP 100、SUR-2和PGC-1）、以前未描述过的与转录复合物相关的其他蛋白（CHD 5、TOG和MORF）和一些命名为PRIC 300、-285、-215、-177和-145的新多肽。我们描述了PRIC 285的cDNA，它包含五个LXXLL基序。它与PPARalpha相互作用，并通过适度刺激转染细胞中PPARalpha介导的转录而作为共激活因子。我们的结论是，配体PPARalpha招聘一个独特的多蛋白复合物从大鼠肝细胞核提取物。该复合物的组成可以提供深入了解组织和物种对过氧化物酶体增殖物的敏感性的基础。
Peroxisome proliferator-activated receptor alpha (PPARalpha) plays a central role in the cell-specific pleiotropic responses induced by structurally diverse synthetic chemicals designated as peroxisome proliferators. Transcriptional regulation by liganded nuclear receptors involves the participation of cofactors that form multiprotein complexes to achieve cell- and gene-specific transcription. Here we report the identification of such a transcriptionally active PPARalpha-interacting cofactor (PRIC) complex from rat liver nuclear extracts that interacts with full-length PPARalpha in the presence of ciprofibrate, a synthetic ligand, and leukotriene B4, a natural ligand. The liganded PPARalpha-PRIC complex enhanced transcription from a peroxisomal enoyl-CoA hydratase/L-3-hydroxyacyl-CoA dehydrogenase bifunctional enzyme gene promoter template that contains peroxisome proliferator response elements. Rat liver PRIC complex comprises some 25 polypeptides, and their identities were established by mass spectrometry and limited sequence analysis. Eighteen of these peptides contain one or more LXXLL motifs necessary for interacting with nuclear receptors. PRIC complex includes known coactivators or coactivator-binding proteins (CBP, SRC-1 PBP, PRIP, PIMT, TRAP100, SUR-2, and PGC-1), other proteins that; have not previously been described in association with transcription complexes (CHD5, TOG, and MORF), and a few novel polypeptides designated PRIC300, -285, -215, -177, and -145. We describe the cDNA for PRIC285, which contains five LXXLL motifs. It interacts with PPARalpha and acts as a coactivator by moderately stimulating PPARalpha-mediated transcription in transfected cells. We conclude that liganded PPARalpha recruits a distinctive multiprotein complex from rat liver nuclear extracts. The composition of this complex may provide insight into the basis of tissue and species sensitivity to peroxisome proliferators.