Arany Zoltan, Wagner Bridget K, Ma Yanhong, Chinsomboon Jessica, Laznik Dina, Spiegelman Bruce M
Dana Farber Cancer Institute and the Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA.
Proc Natl Acad Sci U S A. 2008 Mar 25;105(12):4721-6. doi: 10.1073/pnas.0800979105. Epub 2008 Mar 17.
The transcriptional coactivator PGC-1alpha is a potent regulator of several metabolic pathways, including, in particular, the activation of oxidative phosphorylation and mitochondrial biogenesis. Recent evidence suggests that increasing PGC-1alpha activity may have beneficial effects in various conditions, including muscular dystrophy, diabetes, and neurodegenerative diseases. We describe here a high-throughput screen to identify small molecules that induce PGC-1alpha expression in skeletal muscle cells. A number of drug classes are identified, including glucocorticoids, microtubule inhibitors, and protein synthesis inhibitors. These drugs induce PGC-1alpha mRNA, and the expression of a number of genes known to be regulated by PGC-1alpha. No induction of these target genes is seen in PGC-1alpha -/- cells, demonstrating that the drugs act through PGC-1alpha. These data demonstrate the feasibility of high-throughput screening for inducers of PGC-1alpha. Moreover, the data identify microtubule inhibitors and protein synthesis inhibitors as modulators of PGC-1alpha and oxidative phosphorylation.
转录共激活因子PGC-1α是多种代谢途径的有效调节因子，尤其包括氧化磷酸化的激活和线粒体生物合成。最近的证据表明，提高PGC-1α的活性可能在多种病症中具有有益作用，包括肌肉萎缩症、糖尿病和神经退行性疾病。我们在此描述了一种高通量筛选方法，以鉴定可诱导骨骼肌细胞中PGC-1α表达的小分子。鉴定出了多种药物类别，包括糖皮质激素、微管抑制剂和蛋白质合成抑制剂。这些药物可诱导PGC-1α mRNA以及许多已知受PGC-1α调节的基因的表达。在PGC-1α基因敲除细胞中未观察到这些靶基因的诱导，表明这些药物通过PGC-1α起作用。这些数据证明了高通量筛选PGC-1α诱导剂的可行性。此外，数据确定微管抑制剂和蛋白质合成抑制剂为PGC-1α和氧化磷酸化的调节剂。
