School of Biological Sciences, University of Reading, Whiteknights, Reading RG6 6BX, UK.
Biochem J. 2013 Mar 1;450(2):351-63. doi: 10.1042/BJ20121371.
ERK1/2 (extracellular-signal-regulated kinase 1/2) and their substrates RSKs (p90 ribosomal S6 kinases) phosphorylate different transcription factors, contributing differentially to transcriptomic profiles. In cardiomyocytes ERK1/2 are required for >70% of the transcriptomic response to endothelin-1. In the present study we investigated the role of RSKs in the transcriptomic responses to the G(q)-protein-coupled receptor agonists endothelin-1, phenylephrine (a generic α(1)-adrenergic receptor agonist) and A61603 (α(1A)-adrenergic receptor selective). Phospho-ERK1/2 and phospho-RSKs appeared in cardiomyocyte nuclei within 2-3 min of stimulation (endothelin-1>A61603≈phenylephrine). All agonists increased nuclear RSK2, but only endothelin-1 increased the nuclear RSK1 content. PD184352 (inhibits ERK1/2 activation) and BI-D1870 (inhibits RSKs) were used to dissect the contribution of RSKs to the endothelin-1-responsive transcriptome. Of the 213 RNAs up-regulated after 1 h, 51% required RSKs for their up-regulation, whereas 29% required ERK1/2 but not RSKs. The transcriptomic response to phenylephrine overlapped with, but was not identical with, endothelin-1. As with endothelin-1, PD184352 inhibited the up-regulation of most phenylephrine-responsive transcripts, but the greater variation in the effects of BI-D1870 suggests that differential RSK signalling influences global gene expression. A61603 induced similar changes in RNA expression in cardiomyocytes as phenylephrine, indicating that the signal was mediated largely through α(1A)-adrenergic receptors. A61603 also increased expression of immediate early genes in perfused adult rat hearts and, as in cardiomyocytes, up-regulation of the majority of genes was inhibited by PD184352. PD184352 or BI-D1870 prevented the increased surface area induced by endothelin-1 in cardiomyocytes. Thus RSKs play a significant role in regulating cardiomyocyte gene expression and hypertrophy in response to G(q)-protein-coupled receptor stimulation.
ERK1/2（细胞外信号调节激酶 1/2）及其底物 RSKs（p90 核糖体 S6 激酶）磷酸化不同的转录因子，对转录组图谱产生不同的影响。在心肌细胞中，ERK1/2 对内皮素-1 的转录组反应的贡献超过 70%。在本研究中，我们研究了 RSKs 在 G(q)-蛋白偶联受体激动剂内皮素-1、苯肾上腺素（一种通用的α(1)-肾上腺素能受体激动剂）和 A61603（α(1A)-肾上腺素能受体选择性激动剂）对转录组反应中的作用。磷酸化 ERK1/2 和磷酸化 RSKs 在刺激后 2-3 分钟内出现在心肌细胞核内（内皮素-1>A61603≈苯肾上腺素）。所有激动剂均增加核 RSK2 的含量，但只有内皮素-1增加核 RSK1 的含量。PD184352（抑制 ERK1/2 激活）和 BI-D1870（抑制 RSKs）用于剖析 RSKs 对内皮素-1 反应转录组的贡献。在 1 小时后上调的 213 个 RNA 中，51%需要 RSKs 上调，而 29%需要 ERK1/2 但不需要 RSKs。苯肾上腺素的转录组反应与内皮素-1重叠，但并不完全相同。与内皮素-1一样，PD184352 抑制了大多数苯肾上腺素反应性转录物的上调，但 BI-D1870 的作用变化更大，表明差异 RSK 信号影响全局基因表达。A61603 在心肌细胞中诱导与苯肾上腺素相似的 RNA 表达变化，表明信号主要通过α(1A)-肾上腺素能受体介导。A61603 还增加了灌注成年大鼠心脏中即时早期基因的表达，与心肌细胞一样，大多数基因的上调被 PD184352 抑制。PD184352 或 BI-D1870 可防止内皮素-1诱导的心肌细胞表面积增加。因此，RSKs 在调节心肌细胞基因表达和对 G(q)-蛋白偶联受体刺激的肥大反应中发挥重要作用。
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