SIK1 is a class IIHDAC kinase that promotes survival of skeletal myocytes
SIK1 is a class IIHDAC kinase that promotes survival of skeletal myocytes
复制标题
DOI：
10.1038/nm1573
复制
发表时间：
2007-05-01
期刊：
影响因子：
82.9
通讯作者：
Montminy, Marc
中科院分区：
文献类型：
--
作者：
Berdeaux, Rebecca;Goebel, Naomi;Montminy, Marc
在体育锻炼期间，运动神经元活动的增加通过肌细胞增强因子2（MEF 2）转录因子家族刺激肌肉特异性基因的表达。细胞内钙离子的升高通过II类组蛋白脱乙酰酶（HDAC）的磷酸化依赖性失活来增加MEF 2活性。在确定cAMP反应元件结合蛋白（CREB）在骨骼肌中的作用的研究中，我们发现表达显性负性CREB转基因的小鼠（M-ACREB小鼠）表现出营养不良表型沿着MEF 2活性降低。II类HDAC磷酸化在M-ACREB肌纤维中由于Snf 1 lk（编码盐诱导激酶，SIK 1）的量的减少而减少，所述Snf 1 lk是作为II类HDAC激酶起作用的CREB靶基因。通过病毒表达Snf 1 lk或通过施用小分子拮抗剂来抑制II类HDAC活性改善了M-ACREB小鼠的营养不良表型，指出了SIK 1-HDAC途径在调节肌肉功能中的重要作用。
During physical exercise, increases in motor neuron activity stimulate the expression of muscle-specific genes through the myocyte enhancer factor 2 (MEF2) family of transcription factors. Elevations in intracellular calcium increase MEF2 activity via the phosphorylation-dependent inactivation of class II histone deacetylases (HDACs). In studies to determine the role of the cAMP responsive element binding protein (CREB) in skeletal muscle, we found that mice expressing a dominant-negative CREB transgene (M-ACREB mice) exhibited a dystrophic phenotype along with reduced MEF2 activity. Class II HDAC phosphorylation was decreased in M-ACREB myofibers due to a reduction in amounts of Snf1lk (encoding salt inducible kinase, SIK1), a CREB target gene that functions as a class II HDAC kinase. Inhibiting class II HDAC activity either by viral expression of Snf1lk or by the administration of a small molecule antagonist improved the dystrophic phenotype in M-ACREB mice, pointing to an important role for the SIK1-HDAC pathway in regulating muscle function.