Rsk-2 activity is necessary for epidermal growth factor-induced phosphorylation of CREB protein and transcription of c-fos gene
Rsk-2 activity is necessary for epidermal growth factor-induced phosphorylation of CREB protein and transcription of c-fos gene
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DOI：
10.1073/pnas.95.21.12202
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发表时间：
1998-10-13
影响因子：
11.1
通讯作者：
Sassone-Corsi, P
中科院分区：
文献类型：
--
作者：
De Cesare, D;Jacquot, S;Sassone-Corsi, P
ras依赖性信号级联的生长因子激活导致p90核糖体S6激酶的诱导（p90（风险））。它们被丝裂原激活的蛋白激酶磷酸化后易位到细胞核中，p90（rsk）与细胞质中的p90（rsk）物理相关。在人类中，p90（rsk）家族有三种亚型，rsk -1， rsk -2和Rsk3，它们是不同基因的产物。虽然这些异构体在结构上非常相似，但对它们的功能特异性知之甚少。最近，Rsk-3基因突变与Coffin-Lowry综合征（CLS）有关。我们研究了一种由CLS患者建立的具有无功能的Rsk-2的成纤维细胞系，在这里，我们证明在CLS成纤维细胞中，受表皮生长因子刺激诱导的转录因子CREB （cAMP反应元件结合蛋白）Ser-133磷酸化急剧衰减。效果是特异性的，因为对血清、cAMP和紫外线的反应是不变的。此外，尽管血清反应因子和Elk-1正常磷酸化，但表皮生长因子诱导的c-fos表达在CLS成纤维细胞中严重受损。最后，转染细胞中Rsk-2的共表达通过camp应答元件激活c-fos启动子。因此，我们通过Rsk-2对CREB的磷酸化，在特定生长因子信号的转导与基因表达变化之间建立了联系。
Activation by growth factors of the Ras-dependent signaling cascade results in the induction of p90 ribosomal S6 kinases (p90(rsk)). These are translocated into the nucleus upon phosphorylation by mitogen-activated protein kinases, with which p90(rsk) are physically associated in the cytoplasm, In humans there are three isoforms of the p90(rsk) family, Rsk-1, Rsk-2, and Rsk3, which are products of distinct genes. Although these isoforms are structurally very similar, little is known about their functional specificity. Recently, mutations in the Rsk-3 gene have been associated with the Coffin-Lowry syndrome (CLS). We have studied a fibroblast cell line established from a CLS patient that bears a nonfunctional Rsk-2, Here,ve document that in CLS fibroblasts there is a drastic attenuation in the induced Ser-133 phosphorylation of transcription factor CREB (cAMP response element-binding protein) in response to epidermal growth factor stimulation. The effect is specific, since response to serum, cAMP, and UV light is unaltered. Furthermore, epidermal growth factor-induced expression of c-fos is severely impaired in CLS fibroblasts despite normal phosphorylation of serum response factor and Elk-1, Finally, coexpression of Rsk-2 in transfected cells results in the activation of the c-fos promoter via the cAMP-responsive element. Thus, we establish a link in the transduction of a specific growth factor signal to changes in gene expression via the phosphorylation of CREB by Rsk-2.