Browsing by Subject "Mechanistic target of rapamycin complex 1"

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    The potential of sestrins as therapeutic targets for diabetes
    (Taylor & Francis, 2015-08) Dong, X. Charlie; Department of Biochemistry & Molecular Biology, IU School of Medicine
    Sestrins (Sesn1/2/3) belong to a small protein family that has versatile biological functions. In addition to initially characterized oxidoreductase activity, sestrins also have oxidoreductase-independent functions, including activation of AMP-activated protein kinase, inhibition of the mechanistic target of rapamycin complex 1 (mTORC1) and activation of mTORC2. As these kinases are important for metabolic regulation, sestrins have a favorable profile as potential therapeutic targets for metabolic diseases such as diabetes. Recent data are in line with such a notion. In this editorial, I have attempted to provide a brief update on the major findings in regard to sestrins in metabolism.
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    Protein Kinase A Is a Master Regulator of Physiological and Pathological Cardiac Hypertrophy
    (American Heart Association, 2024) Bai, Yingyu; Zhang, Xiaoying; Li, Ying; Qi, Fei; Liu, Chong; Ai, Xiaojie; Tang, Mingxin; Szeto, Christopher; Gao, Erhe; Hua, Xiang; Xie, Mingxing; Wang, Xuejun; Tian, Ying; Chen, Yongjie; Huang, Guowei; Zhang, Junping; Xiao, Weidong; Zhang, Lili; Liu, Xueyuan; Yang, Qing; Houser, Steven R.; Chen, Xiongwen; Pediatrics, School of Medicine
    Background: The sympathoadrenergic system and its major effector PKA (protein kinase A) are activated to maintain cardiac output coping with physiological or pathological stressors. If and how PKA plays a role in physiological cardiac hypertrophy (PhCH) and pathological CH (PaCH) are not clear. Methods: Transgenic mouse models expressing the PKA inhibition domain (PKAi) of PKA inhibition peptide alpha (PKIalpha)-green fluorescence protein (GFP) fusion protein (PKAi-GFP) in a cardiac-specific and inducible manner (cPKAi) were used to determine the roles of PKA in physiological CH during postnatal growth or induced by swimming, and in PaCH induced by transaortic constriction (TAC) or augmented Ca2+ influx. Kinase profiling was used to determine cPKAi specificity. Echocardiography was used to determine cardiac morphology and function. Western blotting and immunostaining were used to measure protein abundance and phosphorylation. Protein synthesis was assessed by puromycin incorporation and protein degradation by measuring protein ubiquitination and proteasome activity. Neonatal rat cardiomyocytes (NRCMs) infected with AdGFP (GFP adenovirus) or AdPKAi-GFP (PKAi-GFP adenovirus) were used to determine the effects and mechanisms of cPKAi on myocyte hypertrophy. rAAV9.PKAi-GFP was used to treat TAC mice. Results: (1) cPKAi delayed postnatal cardiac growth and blunted exercise-induced PhCH; (2) PKA was activated in hearts after TAC due to activated sympathoadrenergic system, the loss of endogenous PKIα (PKA inhibition peptide α), and the stimulation by noncanonical PKA activators; (3) cPKAi ameliorated PaCH induced by TAC and increased Ca2+ influxes and blunted neonatal rat cardiomyocyte hypertrophy by isoproterenol and phenylephrine; (4) cPKAi prevented TAC-induced protein synthesis by inhibiting mTOR (mammalian target of rapamycin) signaling through reducing Akt (protein kinase B) activity, but enhancing inhibitory GSK-3α (glycogen synthase kinase-3α) and GSK-3β signals; (5) cPKAi reduced protein degradation by the ubiquitin-proteasome system via decreasing RPN6 phosphorylation; (6) cPKAi increased the expression of antihypertrophic atrial natriuretic peptide (ANP); (7) cPKAi ameliorated established PaCH and improved animal survival. Conclusions: Cardiomyocyte PKA is a master regulator of PhCH and PaCH through regulating protein synthesis and degradation. cPKAi can be a novel approach to treat PaCH.