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| The EMBO Journal
(1998) 17, 6649–6659, doi:10.1093/emboj/17.22.6649 |
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| Disruption of the p70s6k/p85s6k gene reveals a small mouse phenotype and a new functional S6 kinase |
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| Hiroshi Shima1, 3, Mario Pende1, 3, Yi Chen2, Stefano Fumagalli1, George Thomas1 and Sara C. Kozma1 |
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1 Friedrich Miescher Institute, Maulbeerstrasse 66, CH-4058 Basel, Switzerland 2 Present address: Laboratory of Gene Regulation and Signal Transduction, Department of Pharmacology, University of California at San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA 3 H.Shima and M.Pende contributed equally to this work To whom correspondence should be addressed George Thomas, gthomas@fmi.ch Sara C. Kozma, kozma@fmi.ch Received 16 July 1998; Revised 22 September 1998; Accepted 24 September 1998. |
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| Abstract |
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| Recent studies have shown that the p70s6k/p85s6k 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 p70s6k/p85s6k 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 p70s6k/p85s6k-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 p70s6k/p85s6k-deficient and wild-type mice. A search of public databases identified a novel p70s6k/p85s6k 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 p70s6k/p85s6k-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 p70s6k/p85s6k function, underscores the importance of S6K function in cell growth. |
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| Keywords: cell growth, kinase, rapamycin, S6 phosphorylation, translational control |
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