Glycogen synthase kinase-3beta is a negative regulator of cardiomyocyte hypertrophy.
Glycogen synthase kinase-3beta is a negative regulator of cardiomyocyte hypertrophy.
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DOI：
10.1083/jcb.151.1.117
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发表时间：
2000-10-02
影响因子：
7.8
通讯作者：
Force, T
中科院分区：
文献类型：
--
作者：
Haq, S;Choukroun, G;Kang, Z B;Ranu, H;Matsui, T;Rosenzweig, A;Molkentin, J D;Alessandrini, A;Woodgett, J;Hajjar, R;Michael, A;Force, T
肥大是对各种应激源和生长因子的基本细胞反应，并且在肌细胞中得到最好的表征。心肌细胞的病理性肥大导致心力衰竭，这是发达国家死亡和残疾的主要原因。一些胞质信号通路已被确定为抑制促肥大信号，但迄今为止，很少有工作集中在信号通路，可能负调节肥大。在此，我们报告了糖原合成酶激酶-3 β（GSK-3β），一种先前与发育和肿瘤发生等多种过程有关的蛋白激酶，通过磷酸肌醇3-激酶依赖性蛋白激酶使GSK-3β在ser 9上磷酸化而被肥大刺激灭活。使用腺病毒介导的GSK-3β基因转移，GSK-3β含有丝氨酸9到丙氨酸的突变，可以防止肥大刺激引起的失活，我们证明GSK-3β的失活是心肌细胞肥大所必需的。此外，我们的数据表明，GSK-3β调节肥大反应，至少部分是通过调节活化T细胞转录因子家族的核因子成员的核/胞质分配。GSK-3β作为抗肥大信号转导子的鉴定表明，可以设计靶向GSK-3通路组分的治疗心脏肥大性疾病的新治疗策略。
Hypertrophy is a basic cellular response to a variety of stressors and growth factors, and has been best characterized in myocytes. Pathologic hypertrophy of cardiac myocytes leads to heart failure, a major cause of death and disability in the developed world. Several cytosolic signaling pathways have been identified that transduce prohypertrophic signals, but to date, little work has focused on signaling pathways that might negatively regulate hypertrophy. Herein, we report that glycogen synthase kinase-3β (GSK-3β), a protein kinase previously implicated in processes as diverse as development and tumorigenesis, is inactivated by hypertrophic stimuli via a phosphoinositide 3-kinase–dependent protein kinase that phosphorylates GSK-3β on ser 9. Using adenovirus-mediated gene transfer of GSK-3β containing a ser 9 to alanine mutation, which prevents inactivation by hypertrophic stimuli, we demonstrate that inactivation of GSK-3β is required for cardiomyocytes to undergo hypertrophy. Furthermore, our data suggest that GSK-3β regulates the hypertrophic response, at least in part, by modulating the nuclear/cytoplasmic partitioning of a member of the nuclear factor of activated T cells family of transcription factors. The identification of GSK-3β as a transducer of antihypertrophic signals suggests that novel therapeutic strategies to treat hypertrophic diseases of the heart could be designed that target components of the GSK-3 pathway.