The Pgc1 family of coactivators has three members: Pgc-1alpha, Pgc-1beta, and PRC. Mitf directly regulates the expression of the master coactivator PGC-1alpha in melanomas ( Haq et al., 2013 Vazquez et al., 2013), while Tfeb participates in lipid metabolism through direct regulation of Pgc-1alpha and Ppar-alpha complex in liver ( Settembre et al., 2013) and functions as a key transcriptional regulator of autophagy ( Settembre et al., 2011). Tfe3 mediates metabolism through the regulation of genes that participate directly in the insulin-signaling pathway ( Nakagawa et al., 2006), through the regulation of lipolysis in adipose tissue ( Fujimoto et al., 2013), and through the regulation of glucose metabolism in skeletal muscle ( Iwasaki et al., 2012). Recently MiT factors have been recognized as major players controlling the expression of key metabolic genes. A significant number of biological and pathological processes are regulated by MiT factors. These factors regulate gene expression by binding in a homo- or hetero-dimeric manner to a specific consensus sequence called E-boxes that resides in promoter regions of target genes ( Beckmann and Kadesch, 1991 Zhao et al., 1993 Steingrimsson et al., 2004). The microphthalmia (MiT) family of basic helix-loop-helix leucine zipper transcription factors includes Mitf, Tfe3, Tfeb, and Tfec family members. Since Pgc-1alpha coactivates numerous biological programs in diverse tissues, the regulation of its expression by upstream transcription factors such Tfe3 implies potential opportunities for the treatment of diseases where modulation of Pgc-1alpha expression may have important clinical outcomes. We conclude that Tfe3 is a critical transcription factor that regulates Pgc-1alpha gene expression in myotubes. This regulation is direct, as shown by Tfe3’s binding to E-boxes on the Pgc-1alpha proximal promoter. Tfe3 ectopic expression induces Pgc-1alpha, and Tfe3 silencing suppresses Pgc-1alpha expression. Our results reported here show that Tfe3 directly regulates Pgc-1alpha expression in myotubes. Tfe3 has not yet been shown to regulate Pgc-1alpha expression. Tfe3 also regulates muscle metabolic genes that enhance insulin sensitivity in skeletal muscle. In skeletal muscle, Pgc-1alpha affects many aspects of muscle functionally such as endurance, fiber-type switching, and insulin sensitivity. Pgc-1alpha is enriched in tissues with high oxidative capacity and plays an important role in the regulation of mitochondrial biogenesis and cellular metabolism. Family members Mitf and Tfeb directly regulate the expression of the master regulator of metabolism, peroxisome-proliferator activated receptor gamma coactivator-1 alpha (Pgc-1alpha), in melanomas and in the liver, respectively.
The microphthalmia (MiT) family of transcription factors is an important mediator of metabolism.
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