title: Identification of transcription factor E3 (TFE3) as a receptor-independent activator of Gα16: gene regulation by nuclear Gα subunit and its activator.
abstract: Receptor-independent G-protein regulators provide diverse mechanisms for signal input to G-protein-based signaling systems, revealing unexpected functional roles for G-proteins. As part of a broader effort to identify disease-specific regulators for heterotrimeric G-proteins, we screened for such proteins in cardiac hypertrophy using a yeast-based functional screen of mammalian cDNAs as a discovery platform. We report the identification of three transcription factors belonging to the same family, transcription factor E3 (TFE3), microphthalmia-associated transcription factor, and transcription factor EB, as novel receptor-independent activators of G-protein signaling selective for Gα(16). TFE3 and Gα(16) were both up-regulated in cardiac hypertrophy initiated by transverse aortic constriction. In protein interaction studies in vitro, TFE3 formed a complex with Gα(16) but not with Gα(i3) or Gα(s). Although increased expression of TFE3 in heterologous systems had no influence on receptor-mediated Gα(16) signaling at the plasma membrane, TFE3 actually translocated Gα(16) to the nucleus, leading to the induction of claudin 14 expression, a key component of membrane structure in cardiomyocytes. The induction of claudin 14 was dependent on both the accumulation and activation of Gα(16) by TFE3 in the nucleus. These findings indicate that TFE3 and Gα(16) are up-regulated under pathologic conditions and are involved in a novel mechanism of transcriptional regulation via the relocalization and activation of Gα(16).
authors: Cardiovascular Research Institute, Yokohama City University School of Medicine, Fukuura, Yokohama 236-0004, Japan. motosato@yokohama-cu.ac.jp
authors: Motohiko
authors: M
authors: Sato
authors: Masahiro
authors: M
authors: Hiraoka
authors: Hiroko
authors: H
authors: Suzuki
authors: Yunzhe
authors: Y
authors: Bai
authors: Reiko
authors: R
authors: Kurotani
authors: Utako
authors: U
authors: Yokoyama
authors: Satoshi
authors: S
authors: Okumura
authors: Mary J
authors: MJ
authors: Cismowski
authors: Stephen M
authors: SM
authors: Lanier
authors: Yoshihiro
authors: Y
authors: Ishikawa
mesh_terms: D000818:Animals; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000096:biosynthesis* / Q000235:genetics; D019556:COS Cells; D006332:Cardiomegaly / Q000235:genetics / Q000378:metabolism*; D002462:Cell Membrane / Q000378:metabolism*; D002522:Chlorocebus aethiops; D057167:Claudins; D043802:GTP-Binding Protein alpha Subunits, Gq-G11 / Q000096:biosynthesis* / Q000235:genetics; D005786:Gene Expression Regulation; D008565:Membrane Proteins / Q000096:biosynthesis; D051379:Mice; D015398:Signal Transduction
chemical_list: D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D057167:Claudins; D008565:Membrane Proteins; C068486:Tcfe3 protein, mouse; C112631:G protein alpha 16; D043802:GTP-Binding Protein alpha Subunits, Gq-G11; C422064:claudin 14