The Activated Glucocorticoid Receptor Modulates Presumptive Autoregulation of Ribosomal Protein S6 Protein Kinase, p70 S6K

Protein metabolism in eukaryotic organisms is defined by a synthesis-degradation equilibrium that is subject to regulation by hormonal and nutritional signals. In mammalian tissues such as skeletal muscle, glucocorticoid hormones specify a catabolic response that influences both protein synthetic an...

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Bibliographic Details
Published in:The Journal of biological chemistry 2002-01, Vol.277 (4), p.2525-2533
Main Authors: Shah, O. Jameel, Iniguez-Lluhi, Jorge A., Romanelli, Angela, Kimball, Scot R., Jefferson, Leonard S.
Format: Article
Language:English
Subjects:
Animals
Blotting, Western
Cell Line
CHO Cells
COS Cells
Cricetinae
Dexamethasone - pharmacology
DNA - metabolism
DNA Mutational Analysis
DNA, Complementary - metabolism
Epitopes
Glucocorticoids - metabolism
Humans
Mifepristone - pharmacology
Models, Biological
Phosphorylation
Protein Binding
Protein Biosynthesis
Protein Structure, Tertiary
Rats
Receptors, Glucocorticoid - metabolism
Ribosomal Protein S6 Kinases - metabolism
RNA, Messenger - metabolism
S6 kinase
Serine - chemistry
Threonine - chemistry
Time Factors
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Summary:Protein metabolism in eukaryotic organisms is defined by a synthesis-degradation equilibrium that is subject to regulation by hormonal and nutritional signals. In mammalian tissues such as skeletal muscle, glucocorticoid hormones specify a catabolic response that influences both protein synthetic and protein degradative pathways. With regard to the former, glucocorticoids attenuate mRNA translation at two levels: translational efficiency, i.e.translation initiation, and translational capacity, i.e.ribosome biogenesis. Glucocorticoids may impair translational capacity through the ribosomal S6 protein kinase (p70 S6K), a recognized glucocorticoid target and an effector of ribosomal protein synthesis. We demonstrate here that the reduction in growth factor-activated p70 S6K activity by glucocorticoids depends upon a functional glucocorticoid receptor (GR) and that the GR is both necessary and sufficient to render p70 S6K subject to glucocorticoid regulation. Furthermore, the DNA binding and transcriptional activation but not repression properties of the GR are indispensable for p70 S6K regulation. Finally, a mutational analysis of the p70 S6K carboxyl terminus indicates that this region confers glucocorticoid sensitivity, and thus glucocorticoids may facilitate autoinhibition of the enzyme ultimately reducing the efficiency with which T389 is phosphorylated.
ISSN:0021-9258
1083-351X
DOI:10.1074/jbc.M105935200