Disruption of the p70s6k/p85s6k gene reveals a small mouse phenotype and a new functional S6 kinase

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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