p70 S6 kinase (p70s6k) and its nuclear isoform p85s6k, which are proposed to phosphorylate ribosomal S6 protein in higher eukaryotes, are inactivated in quiescent cells and activated by any of the known mitogenic stimuli for quiescent cells to enter the cell division cycle. In fact, the inhibition of p70/85s6k by a specific inhibitor, rapamycin (RAP), or by micro-injection of an antibody against p70/85s6k, results in either G1 arrest or G1 prolongation when resting cells enter the cell cycle. The applicant's studies demonstrated that addition of RAP resulted in a rapid and selective inhibition of the synthesis of ribosomal proteins, including elongation factors (r-proteins) at the level of translation. Levels of activity of p70/85s6k and their inhibition by RAP correlated with the rate of biosynthesis of elongation factor 2, suggesting that activation of p70/85s6k may selectively facilitate the translation of mRNAs encoding r-proteins. Interestingly, mRNAs encoding r-proteins in higher eukaryotes have a highly conserved structure at their 5'-terminus (cytidine-pyrimidine tract), indicating that these mRNAs may be specifically and coordinately regulated. It is possible that activation of p70/85s6k may facilitate the selective translation of r-protein mRNAs which have the consensus sequence at the 5'-end. In this proposal the applicant will test the possible linkage of p70s6k and p85s6k activity to the translational regulation of r-protein mRNA by multiple approaches. The studies may elucidate the role of p70/85s6k as supporting cell growth by increasing r-protein mRNAs' translation. This would be an important discovery in the studies of protein kinases as well as in the studies of mRNA translation. In addition to the significance for basic cellular biology, this association between the kinase and r-protein synthesis may open a novel therapeutic potential for the specific inhibitor of the kinase, rapamycin, as a modulator of protein synthesis.
