Disruption of the p70s6k/p85s6k gene reveals a small mouse phenotype and a new functional S6 kinase
Disruption of the p70s6k/p85s6k gene reveals a small mouse phenotype and a new functional S6 kinase
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DOI：
10.1093/emboj/17.22.6649
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发表时间：
1998-11-16
期刊：
影响因子：
11.4
通讯作者：
Kozma, SC
中科院分区：
文献类型：
--
作者：
Shima, H;Pende, M;Kozma, SC
最近的研究表明，p70（s6 k）/p85（s6 k）信号通路通过调节称为5 'TOPs的mRNA家族的翻译在细胞生长中起关键作用，所述5' TOPs编码蛋白质合成装置的组分。在这里，我们证明了p70（s6 k）/p85（s6 k）基因的纯合破坏不影响小鼠的生存能力或生育能力，但它对动物的生长，特别是在胚胎发育过程中有显着的影响。令人惊讶的是，S6磷酸化在肝脏或成纤维细胞从p70（s6 k）/p85（s6 k）缺陷小鼠正常进行有丝分裂原刺激的反应。此外，血清诱导的S6磷酸化和5 'TOP mRNA的翻译上调对来自p70（s6 k）/p85（s6 k）缺陷型和野生型小鼠的小鼠胚胎成纤维细胞中雷帕霉素的抑制作用同样敏感。通过对公共数据库的检索，鉴定出一种新的p70（s6 k）/p85（s6 k）同源物，其含有已知控制激酶活性的相同调控基序和磷酸化位点。这种新鉴定的基因产物，称为S6 K2，是普遍表达的，并显示有丝分裂原依赖性和雷帕霉素敏感的S6激酶活性。更引人注目的是，在p70（s6 k）/p85（s6 k）缺陷小鼠中，S6 K2基因在所有检查的组织中上调，特别是在胸腺中，雷帕霉素作用的主要靶点。新的S6激酶基因的发现，可以部分补偿p70（s6 k）/p85（s6 k）功能，强调了S6 K功能在细胞生长中的重要性。
Recent studies have shown that the p70(s6k)/p85(s6k) signaling pathway plays a critical role in cell growth by modulating the translation of a family of mRNAs termed 5'TOPs, which encode components of the protein synthetic apparatus. Here we demonstrate that homozygous disruption of the p70(s6k)/p85(s6k) gene does not affect viability or fertility of mice, but that it has a significant effect on animal growth, especially during embryogenesis. Surprisingly, S6 phosphorylation in liver or in fibroblasts from p70(s6k)/p85(s6k)-deficient mice proceeds normally in response to mitogen stimulation. Furthermore, serum-induced S6 phosphorylation and translational up-regulation of 5'TOP mRNAs were equally sensitive to the inhibitory effects of rapamycin in mouse embryo fibroblasts derived from p70(s6k)/p85(s6k)-deficient and wild-type mice. A search of public databases identified a novel p70(s6k)/p85(s6k) homolog which contains the same regulatory motifs and phosphorylation sites known to control kinase activity. This newly identified gene product, termed S6K2, is ubiquitously expressed and displays both mitogen-dependent and rapamycin-sensitive S6 kinase activity. More striking, in p70(s6k)/p85(s6k)-deficient mice, the S6K2 gene is up-regulated in all tissues examined, especially in thymus, a main target of rapamycin action. The finding of a new S6 kinase gene, which can partly compensate for p70(s6k)/p85(s6k) function, underscores the importance of S6K function in cell growth.