Differential activation of p70 and p85 S6 kinase isoforms during cardiac hypertrophy in the adult mammal
Differential activation of p70 and p85 S6 kinase isoforms during cardiac hypertrophy in the adult mammal
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DOI：
10.1074/jbc.273.38.24610
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发表时间：
1998-09-18
影响因子：
4.8
通讯作者：
Kuppuswamy, D
中科院分区：
文献类型：
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作者：
Laser, M;Kasi, VS;Kuppuswamy, D
采用成年猫右心室压力超负荷(RVPO)模型，研究了参与翻译和转录激活的两种S6激酶(S6K)亚型p70(S6K)和P85(S6K)。心肌细胞水平的生化和共聚焦显微镜分析表明，p70(S6K)主要存在于胞浆中，在1h的RVPO中大量激活(>；12倍)，并在Ser-411、Thr-421和Ser-424的假底物结构域中被磷酸化。仅定位于胞核的p85(S6K)在p70(S6K)之后被激活。在p70(S6K)、Thr-421和Ser-424等位点，RVPO的磷酸化持续增加到48h，但在Ser-411处没有。两种异构体都没有在胞浆和细胞核之间转移。进一步的研究发现：(I)蛋白激酶C亚型(α、γ和epsilon)和c-Raf的激活过程相似，(Ii)没有伴随的磷脂酰肌醇S激酶的激活，(Iii)p70(S6K)后c-Src的激活，以及(Iv)12-O-十四酰佛波醇-13-乙酸酯处理后成人心肌细胞的相似变化。因此，这些研究表明，在心肌肥厚中，蛋白激酶C介导的途径通过S6K亚型的差异激活将压力超负荷与生长诱导相结合。
An adult feline right ventricular pressure overload (RVPO) model was used to examine the two S6 kinase (S6K) isoforms, p70(S6K) and p85(S6K), that are involved in translational and transcriptional activation. Biochemical and confocal microscopy analyses at the level of the cardiocyte revealed that p70(S6K) is present predominantly in the cytosol, substantially activated in 1-h RVPO (>12 fold), and phosphorylated in the pseudosubstrate domain at the Ser-411, Thr-421, and Ser-424 sites. p85(S6K), which was localized exclusively in the nucleus, showed activation subsequent to p70(S6K). With a sustained increase in phosphorylation for up to 48 h of RVPO at equivalent sites of p70(S6K), Thr-421 and Ser-424, but not at Ser-411. Neither isoform translocated between the cytosol and the nucleus. Further studies to determine potential upstream elements of S6K activation revealed: (i) similar time course of activation for protein kinase C isoforms (alpha, gamma, and epsilon) and c-Raf, (ii) absence of accompanying phosphatidylinositol S-kinase activation, (iii) activation of c-Src subsequent to p70(S6K), and (iv) similar changes in adult cardiocytes after treatment with 12-O-tetradecanoylphorbol-13-acetate. Thus, these studies suggest that a protein kinase C-mediated pathway couples pressure overload to growth induction via differential activation of S6K isoforms in cardiac hypertrophy.