Abstract 14838: Novel Transcription Regulation in the Hypertrophied Myocardium via Nuclear Galpha16 Subunit and Activator of G-Protein Signaling (AGS)
Cell signaling via heterotrimeric G-proteins is involved in the development of cardiac hypertrophy. In addition to G-protein coupled receptors, there exist receptor-independent regulators for heterotrimeric G-proteins which provide alternative signal input that may be involved in the adaptation process of cells to various stresses. As a part of an effort to identify such entities in cardiovascular diseases, we used a functional screen to identify receptor-independent activators of G-protein signaling (AGS) in the hypertrophied mouse heart induced by transverse aortic constriction. We identified three MITF/TFE transcription factors, TFE3, MITF, and TFEB, as novel AGS proteins for Gα16. TFE3 formed a complex with Gα16 but not Gαi3, Gαs, or Gαq in cells. TFE3 activated Gα16 in the absence of receptor stimulation but not other Gα subunits. TFE3 had no influence on receptor-mediated Gα16 signaling in the plasma membrane, however, TFE3 induced translocation of Gα16 to the nucleus. Interestingly, the accumulation of TFE3/Gα16 in the nucleus induced the expression of claudin 14 (133.1 ± 34.6 fold, p<0.05 vs. control, mean±SEM), which was a key component of membrane structure in cardiomyocytes. Caludin 14 was not induced by TFE3 mutant, unable to activate Gα16 or by the inactive mutant of Gα16, suggesting that the activation of nuclear Gα16 by TFE3 was required for the caludin 14 induction. Upon pressure overload stress by transverse aortic constriction, claudin 14 was increased (4.9 ± 1.3 fold, p<0.05 vs. sham control, mean±SEM) with accompanying upregulation of TFE3 (2.0 ± 0.65 fold, p<0.05 vs. sham control, mean±SEM) and Gα16 (4.4 ± 0.26 fold, p<0.05 vs. sham control, mean±SEM) in the mouse heart. Taken together, TFE3 transcription factor is a new AGS for Gα16, that appears to generate a TEF3-Gα16 complex in the nucleus that drives the transcription of claudin 14. Our findings suggest the existence of a novel mechanism of transcriptional regulation under pressure overload stress via the relocalization/activation of Gα subunit with specific AGS proteins.
- © 2010 by American Heart Association, Inc.