Yoshioka Toyo, Inagaki Kenjiro, Noguchi Tetsuya, Sakai Mashito, Ogawa Wataru, Hosooka Tetsuya, Iguchi Haruhisa, Watanabe Eijiro, Matsuki Yasushi, Hiramatsu Ryuji, Kasuga Masato
Department of Internal Medicine, Kobe University Graduate School of Medicine, Chuo-ku, Japan.
Biochem Biophys Res Commun. 2009 Apr 17;381(4):537-43. doi: 10.1016/j.bbrc.2009.02.077. Epub 2009 Feb 20.
The transcriptional regulator peroxisome proliferator-activated receptor-gamma coactivator-1alpha (PGC-1alpha) controls mitochondrial biogenesis and energy homeostasis. Although physical exercise induces PGC-1alpha expression in muscle, the underlying mechanism of this effect has remained incompletely understood. We recently identified a novel muscle-enriched isoform of PGC-1alpha transcript (designated PGC-1alpha-b) that is derived from a previously unidentified first exon. We have now cloned and characterized the human PGC-1alpha-b promoter. The muscle-specific transcription factors MyoD and MRF4 transactivated this promoter through interaction with a proximal E-box motif. Furthermore, either forced expression of Ca(2+)- and calmodulin-dependent protein kinase IV (CaMKIV), calcineurin A, or the p38 mitogen-activated protein kinase (p38 MAPK) kinase MKK6 or the intracellular accumulation of cAMP activated the PGC-1alpha-b promoter in cultured myoblasts through recruitment of cAMP response element (CRE)-binding protein (CREB) to a putative CRE located downstream of the E-box. Our results thus reveal a potential molecular basis for isoform-specific regulation of PGC-1alpha expression in contracting muscle.
转录调节因子过氧化物酶体增殖物激活受体γ共激活因子1α（PGC-1α）控制线粒体生物合成和能量稳态。尽管体育锻炼可诱导肌肉中PGC-1α的表达，但其潜在机制仍未完全明确。我们最近鉴定出一种新的富含肌肉的PGC-1α转录本异构体（命名为PGC-1α-b），它来源于一个先前未被识别的第一外显子。我们现已克隆并鉴定了人PGC-1α-b启动子。肌肉特异性转录因子MyoD和MRF4通过与近端E盒基序相互作用反式激活该启动子。此外，强制表达钙调蛋白依赖性蛋白激酶IV（CaMKIV）、钙调神经磷酸酶A或p38丝裂原活化蛋白激酶（p38 MAPK）激酶MKK6，或细胞内cAMP的积累，均可通过募集cAMP反应元件（CRE）结合蛋白（CREB）至E盒下游的假定CRE，从而激活培养的成肌细胞中的PGC-1α-b启动子。因此，我们的结果揭示了收缩肌肉中PGC-1α表达的异构体特异性调控的潜在分子基础。
