Positive transcription elongation factor b activity in compensatory myocardial hypertrophy is regulated by cardiac lineage protein-1.
Positive transcription elongation factor b activity in compensatory myocardial hypertrophy is regulated by cardiac lineage protein-1.
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DOI：
10.1161/circresaha.108.191726
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发表时间：
2009-06-19
影响因子：
20.1
通讯作者：
Siddiqui MA
中科院分区：
文献类型：
--
作者：
Espinoza-Derout J;Wagner M;Salciccioli L;Lazar JM;Bhaduri S;Mascareno E;Chaqour B;Siddiqui MA
新出现的证据说明了正转录延伸因子B（P-TEF B）在控制总体RNA合成中的重要性，总体RNA合成构成心肌细胞对各种肥大刺激的代偿反应的主要特征。由细胞周期蛋白T和cdk 9组成的P-TEFb复合物对于通过RNA聚合酶II（CTD RNA Pol II）的羧基末端结构域的磷酸化来延长新生RNA链至关重要。我们和其他人已经表明，在各种生理和病理条件下，P-TEFb的活性被其与CLP-1（人HEXIM 1的小鼠同源物）的结合所抑制。为了研究CLP-1在心肌肥大中控制P-TEFb活性的机制，我们使用了由心肌中钙调神经磷酸酶过表达引起的肥大转基因小鼠模型。我们观察到与P-TEFb相关的CLP-1水平在肥厚心脏中显著降低。我们还通过将MHC-cyclin T1转基因小鼠与CLP-1杂合子杂交产生了双基因小鼠（MHC-cyclin T1/CLP-1+/−）。双基因小鼠表现出对肥大的易感性增强，这伴随着通过CTD的丝氨酸2磷酸化增加和GLUT 1/GLUT 4比率增加而增加的cdk 9活性。这些小鼠具有代偿性收缩功能，没有纤维化和寿命缩短的证据。这些数据表明，在细胞周期蛋白T1水平升高的背景下引入的CLP-1水平降低提高了P-TEFb活性的去抑制，并强调了CLP-1在心肌细胞代偿性肥大机制中的作用的重要性。
Emerging evidence illustrates the importance of the Positive Transcription Elongation Factor b (P-TEFb) in control of global RNA synthesis which constitutes a major feature of the compensatory response to diverse hypertrophic stimuli in cardiomyocytes. P-TEFb complex, composed of cyclin T and cdk9, is critical for elongation of nascent RNA chains via phosphorylation of the carboxyl terminal domain of RNA polymerase II (CTD RNA Pol II). We and others have shown that the activity of P-TEFb is inhibited by its association with CLP-1, the mouse homolog of human HEXIM1, in various physiological and pathological conditions. To investigate the mechanism of CLP-1’s control of the P-TEFb activity in cardiac hypertrophy, we used a transgenic mouse model of hypertrophy caused by over-expression of calcineurin in the heart. We observed that the level of CLP-1 associated with P-TEFb was reduced markedly in hypertrophic hearts. We also generated bigenic mice (MHC-cyclin T1/CLP-1+/−) by crossing MHC-cyclin T1 transgenic mice with CLP-1 heterozygote. The bigenic mice exhibit enhanced susceptibility to hypertrophy which is accompanied with an increase in cdk9 activity via an increase in serine 2 phosphorylation of CTD and an increase in GLUT1/GLUT4 ratio. These mice have compensated systolic function without evidence of fibrosis and reduced life span. These data suggest that the reduced level of CLP-1 introduced in the background of elevated levels of cyclin T1 elevates de-repression of P-TEFb activity and emphasizes the importance of CLP-1’s role in the mechanism governing compensatory hypertrophy in cardiomyocytes.