S6 Kinase: Mechanism of activation and its role in the proliferative response

摘要

In recent times, interest in how signal transduction pathways, which control cell growth, integrate, with those, that control cell cycle progression has intensified. Upregulation of the activity of the translational machinery is a necessary step in both cell growth and cell proliferation (see Montagne et al., this volume). The 40S ribosomal protein S6 kinase (S6K), through phosphorylation of its substrate, has been implicated in the regulation of the translation of 5'TOP mRNAs, a family of transcripts encoding mainly for components of the protein synthetic apparatus. Inhibition of mitogen-induced S6K1 activation in vivo with either neutralising antibodies or by treatment with the immunosuppressant rapamycin inhibits Gl progression [1,2]. Cloning of S6K from mice revealed two isoforms. A shorter, cytoplasmic form (p70~(S6K)) and a larger nuclear form (p85~(S6K)) [3]. Both isoforms are generated from alternative translation start sites from the same transcript and appear to be largely co-ordinately regulated. Homozygous disruption of the S6K gene does not affect viability or fertility of mice, but it has a significant effect on animal growth, especially during embryogenesis. Surprisingly, S6 phosphorylation in liver or in fibroblasts from S6K deficient mice proceeds normally in response to mitogen stimulation. Furthermore serum induced S6 phosphorylation and the translational upregulation of 5'TOP mRNAs, was as sensitive to the inhibitory effects of the immunosuppressant rapamycin in mouse embryo fibroblasts derived from S6K deficient mice as from wild-type mice. The observation that deletion of the S6K gene in mice did not impair either S6 phosphorylation or 5'TOP mRNA translation, led to the identification of a second S6 kinase gene which is highly homologous to the first gene [4-6], For simplicity p70~(S6k)/p85~(S6K) and the new S6 kinase gene have been termed S6K1 and S6K2, respectively. Both isoforms appear to be ubiquitously expressed and in S6K1 deficient mice the S6K2 gene is upregulated in all tissues examined, especially in thymus, a main target of rapamycin action. This lecture will mainly focus on the activation mechanism of S6K1, its role in translation and the pathways regulating its activity.