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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Distinct roles of GSK-3 alpha and GSK-3 beta phosphorylation in the heart under pressure overload
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Distinct roles of GSK-3 alpha and GSK-3 beta phosphorylation in the heart under pressure overload

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摘要

Glycogen synthase kinase-3 (GSK-3) is a master regulator of growth and death in cardiac myocytes. GSK-3 is inactivated by hypertrophic stimuli through phosphorylation-dependent and -independent mechanisms. Inactivation of GSK-3 removes the negative constraint of GSK-3 on hypertrophy, thereby stimulating cardiac hypertrophy. N-terminal phosphorylation of the GSK-3 isoforms GSK-3 alpha and GSK-3 beta by upstream kinases (e. g., Akt) is a major mechanism of GSK-3 inhibition. Nonetheless, its role in mediating cardiac hypertrophy and failure remains to be established. Here we evaluated the role of Serine(S) 21 and S9 phosphorylation of GSK-3 alpha and GSK-3 beta in the regulation of cardiac hypertrophy and function during pressure overload (PO), using GSK-3 alpha S21A knock-in (alpha KI) and GSK-3 alpha S9A knock-in (beta KI) mice. Although inhibition of S9 phosphorylation during PO in the beta KI mice attenuated hypertrophy and heart failure (HF), inhibition of S21 phosphorylation in the alpha KI mice unexpectedly promoted hypertrophy and HF. Inhibition of S21 phosphorylation in GSK-3 alpha, but not of S9 phosphorylation in GSK-3 beta, caused phosphorylation and down-regulation of G1-cyclins, due to preferential localization of GSK-3 alpha in the nucleus, and suppressed E2F and markers of cell proliferation, including phosphorylated histone H3, under PO, thereby contributing to decreases in the total number of myocytes in the heart. Restoration of the E2F activity by injection of adenovirus harboring cyclin D1 with a nuclear localization signal attenuated HF under PO in the alpha KI mice. Collectively, our results reveal that whereas S9 phosphorylation of GSK-3 beta mediates pathological hypertrophy, S21 phosphorylation of GSK-3 alpha plays a compensatory role during PO, in part by alleviating the negative constraint on the cell cycle machinery in cardiac myocytes.

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