Disruption of the p70(s6k)/p85(s6k) gene reveals a small mouse phenotype and a new functional S6 kinase

Recent studies have shown that the p70(s6k)/p85(s6k) signaling pathway play s 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 ap paratus. 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. Sur prisingly, S6 phosphorylation in liver or in fibroblasts from p70(s6k)/p85( s6k)-deficient mice proceeds normally in response to mitogen stimulation. F urthermore, serum-induced S6 phosphorylation and translational up-regulatio n of 5'TOP mRNAs were equally sensitive to the inhibitory effects of rapamy cin in mouse embryo fibroblasts derived from p70(s6k)/p85(s6k)-deficient an d wild-type mice. A search of public databases identified a novel p70(s6k)/ p85(s6k) homolog which contains the same regulatory motifs and phosphorylat ion sites known to control kinase activity. This newly identified gene prod uct, termed S6K2, is ubiquitously expressed and displays both mitogen-depen dent and rapamycin-sensitive S6 kinase activity. More striking, in p70(s6k) /p85(s6k)-deficient mice, the S6K2 gene is up-regulated in all tissues exam ined, 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.