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首页> 外文期刊>Molecular and Cellular Biology >Deficient Gene Expression in Protein Kinase Inhibitor α Null Mutant Mice
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Deficient Gene Expression in Protein Kinase Inhibitor α Null Mutant Mice

机译:蛋白激酶抑制剂α空突变小鼠基因表达不足。

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Protein kinase inhibitor (PKI) is a potent endogenous inhibitor of the cyclic AMP (cAMP)-dependent protein kinase (PKA). It functions by binding the free catalytic (C) subunit with a high affinity and is also known to export nuclear C subunit to the cytoplasm. The significance of these actions with respect to PKI's physiological role is not well understood. To address this, we have generated by homologous recombination mutant mice that are deficient in PKIα, one of the three isoforms of PKI. The mice completely lack PKI activity in skeletal muscle and, surprisingly, show decreased basal and isoproterenol-induced gene expression in muscle. Further examination revealed reduced levels of the phosphorylated (active) form of the transcription factor CREB (cAMP response element binding protein) in the knockouts. This phenomenon stems, at least in part, from lower basal PKA activity levels in the mutants, arising from a compensatory increase in the level of the RIα subunit of PKA. The deficit in gene induction, however, is not easily explained by current models of PKI function and suggests that PKI may play an as yet undescribed role in PKA signaling.
机译:蛋白激酶抑制剂(PKI)是环状AMP(cAMP)依赖性蛋白激酶(PKA)的有效内源性抑制剂。它通过以高亲和力结合游离的催化(C)亚基而起作用,并且还已知将核C亚基输出到细胞质。关于PKI的生理作用,这些作用的重要性尚不十分清楚。为了解决这个问题,我们通过同源重组突变小鼠产生了PKIα(PKI的三种同工型之一)缺失的小鼠。小鼠在骨骼肌中完全缺乏PKI活性,令人惊讶的是,它们在肌肉中显示出基础和异丙肾上腺素诱导的基因表达降低。进一步的检查表明,敲除物中磷酸化(活性)形式的转录因子CREB(cAMP反应元件结合蛋白)水平降低。这种现象至少部分源于突变体中较低的基础PKA活性水平,这是由于PKARIα亚基水平的补偿性增加引起的。然而,目前的PKI功能模型不容易解释基因诱导的缺陷,并提示PKI在PKA信号传导中可能起尚未描述的作用。

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