Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:2.7.11.27 (AMPK)
 6,299 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In mammals, the sestrin family is composed of three stress-responsive genes. Ablation of sestrin in Drosophila attenuates longevity, which is accompanied by increased S6K phosphorylation and decreased AMPK phosphorylation. Nevertheless, the metabolic role of sestrins in mammals is not comprehensively understood. We characterized the expression of individual sestrin family members and determined their role in vastus lateralis muscle biopsies from participants with normal glucose tolerance (NGT) or type 2 diabetes (T2D). Expression of sestrin 1 or sestrin 2 mRNA was unaltered between the NGT and T2D participants. Conversely, sestrin 3 mRNA was increased in T2D patients and correlated with fasting plasma glucose, 2-h postprandial plasma glucose and HbA1c. A trend for increased sestrin 3 protein was observed in T2D patients. In human primary myotubes, sestrin 3 mRNA increased during differentiation, and this response was unaltered in T2D-derived myotubes. Long-term treatment of myotubes with insulin or AICAR decreased sestrin 3 mRNA. Exposure of myotubes to the reactive oxygen species H2O2 increased mRNA expression of sestrin 1 and 2, whereas sestrin 3 was unaltered. siRNA-mediated silencing of sestrin 3 in myotubes was without effect on insulin-stimulated glucose incorporation into glycogen or AICAR-stimulated palmitate oxidation. These results provide evidence against sestrin 3 in the direct control of glucose or lipid metabolism in human skeletal muscle. However, siRNA-mediated sestrin 3 gene silencing in myotubes increased myostatin expression. Collectively, our results indicate sestrin 3 is upregulated in T2D and could influence skeletal muscle differentiation without altering glucose and lipid metabolism.
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PMID:Sestrin 3 regulation in type 2 diabetic patients and its influence on metabolism and differentiation in skeletal muscle. 2412 97

Doxorubicin is a chemotherapy medication widely used to treat a variety of cancers. Even though it offers one of the most effective anti-cancer treatments, its clinical use is limited because of its strong cardiotoxicity that can lead to fatal conditions. Here, we show that sestrin 1 and sestrin 2, members of the sestrin family of proteins that are stress-inducible regulators of metabolism, are critical for suppressing doxorubicin cardiotoxicity and coordinating the AMPK-mammalian target of rapamycin complex 1 (mTORC1) autophagy signaling network for cardioprotection. Expression of both sestrin 1 and sestrin 2 was highly increased in the mouse heart after doxorubicin injection. Genetic ablation of sestrin 1 and sestrin 2 rendered mice more vulnerable to doxorubicin and exacerbated doxorubicin-induced cardiac pathologies including cardiomyocyte apoptosis and cardiac dysfunction. These pathologies were associated with strong dysregulation of the cardiac signaling network, including suppression of the AMPK pathway and activation of the mTORC1 pathway. Consistent with AMPK downregulation and mTORC1 upregulation, autophagic activity of heart tissue was diminished, leading to prominent accumulation of autophagy substrate, p62/SQSTM1. Taken together, our results indicate that sestrin 1 and sestrin 2 are important cardioprotective proteins that coordinate metabolic signaling pathways and autophagy to minimize cardiac damage in response to doxorubicin insult. Augmenting this protective mechanism could provide a novel therapeutic rationale for prevention and treatment of doxorubicin cardiotoxicity. NEW & NOTEWORTHY Doxorubicin is a highly efficient chemotherapeutic medicine; however, its use is limited because of its strong cardiotoxicity. Here, we show that sestrin 1 and sestrin 2 are critical protectors of cardiomyocytes from doxorubicin damage. By upregulating AMPK and autophagic activities and suppressing mammalian target of rapamycin complex 1 and oxidative stress, sestrins counteract detrimental effects of doxorubicin on cardiomyocytes. Correspondingly, loss of sestrin 1 and sestrin 2 produced remarkable dysregulation of these pathways, leading to prominent cardiac cell death and deterioration of heart function.
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PMID:Cardioprotective roles of sestrin 1 and sestrin 2 against doxorubicin cardiotoxicity. 3102 86