Characterization of the transactivation domain in the peroxisome-proliferator-activated receptor gamma co-activator (PGC-1).
Characterization of the transactivation domain in the peroxisome-proliferator-activated receptor gamma co-activator (PGC-1).
复制标题
过氧化物酶体增殖物激活受体 γ 共激活剂 (PGC-1) 反式激活结构域的表征。
DOI：
10.1042/bj20061526
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发表时间：
2007
期刊：
影响因子：
--
通讯作者：
Park,EdwardsA
中科院分区：
文献类型：
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作者：
Sadana,Prabodh;Park,EdwardsA
PGC-1 s（peroxisome-proliferator-activated receptor γ co-activators）是一个转录调节因子家族，可诱导多种代谢基因的表达。PGC-1蛋白刺激参与线粒体生物合成、脂肪酸氧化和肝细胞生成的基因。先前的研究表明PGC-1α和β亚型通过保守的LXXLL（leucine-X-X-leucine-leucine）基序与核受体相互作用。在本研究中，我们研究了这些PGC-1亚型刺激基因表达的机制。我们已经确定PGC-1的N-末端负责转录激活。在PGC-1α和β亚型的N-末端鉴定出两个保守的肽基序。这些结构域被命名为AD 1和AD 2（激活结构域1和2）。这两个基序的缺失减少了各种PGC-1调节基因的诱导，包括PEPCK（磷酸烯醇丙酮酸羧激酶）和CPT-I（肉毒碱棕榈酰转移酶-I）基因。已确定AD 1中含有负电荷的氨基酸和AD 2中的亮氨酸残基对于PEPCK和CPT-1基因的转录诱导是重要的。AD基序的破坏不会降低PGC-1α蛋白与PEPCK或CPT-I基因结合的能力。此外，AD结构域的缺失并没有消除PGC-1α与甲状腺激素受体相互作用的能力。这些数据表明，AD 1和AD 2基序介导了许多PGC-1应答基因的诱导，但它们并不有助于PGC-1向靶基因的募集。
The PGC-1s (peroxisome-proliferator-activated receptor γ co-activators) are a family of transcriptional regulators that induce the expression of various metabolic genes. PGC-1 proteins stimulate genes involved in mitochondrial biogenesis, fatty acid oxidation and hepatic gluconeogenesis. Previous studies have demonstrated that the PGC-1α and β isoforms interact with nuclear receptors through the conserved LXXLL (leucine-X-X-leucine-leucine) motifs. In the present study, we have investigated the mechanisms by which these PGC-1 isoforms stimulate gene expression. We have determined that the N-terminus of PGC-1 is responsible for transcriptional activation. Two conserved peptide motifs were identified in the N-terminus of PGC-1α and β isoforms. These domains were named AD1 and AD2 (activation domain 1 and 2). Deletion of both of these motifs decreased the induction of various PGC-1-regulated genes including the PEPCK (phosphoenolpyruvate carboxykinase) and CPT-I (carnitine palmitoyltransferase-I) genes. It was determined that amino acids containing a negative charge in AD1 and the leucine residues in AD2 were important for the transcriptional induction of the PEPCK and CPT-I genes. Disruption of the AD motifs did not diminish the ability of the PGC-1α protein to associate with the PEPCK or CPT-I genes. In addition, deletion of the AD domains did not eliminate the ability of PGC-1α to interact with the thyroid hormone receptor. The data indicate that the AD1 and AD2 motifs mediate the induction of many PGC-1- responsive genes, but they do not contribute to the recruitment of PGC-1 to target genes.