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J. Biol. Chem., Vol. 277, Issue 4, 2525-2533, January 25, 2002
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From the 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.
The Activated Glucocorticoid Receptor Modulates Presumptive
Autoregulation of Ribosomal Protein S6 Protein Kinase, p70
S6K*
,, and
Department of Cellular and Molecular
Physiology, Pennsylvania State University College of Medicine, Hershey,
Pennsylvania 17033-0850, § Department of Pharmacology,
University of Michigan School of Medicine, Ann Arbor, Michigan 48109, and the ¶ Department of Cell Biology, Harvard Medical School,
Boston, Massachusetts 02115
*
This work was supported by National Institutes of Health
Grants DK-15658 (to L. S. J.) and T32-GM-08619 (O. J. S.).The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
To whom correspondence should be addressed: Dept. of Cellular
and Molecular Physiology, Pennsylvania State University College of
Medicine, 500 University Dr., Hershey, PA 17033-0850. Tel.: 717-531-8567; Fax: 717-531-7667; E-mail: jjefferson@psu.edu.
Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.
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