Mouse Glucocorticoid Receptor Phosphorylation Status Influences Multiple Functions of the Receptor Protein

Webster, Jeffrey C.; Jewell, Christine M.; Bodwell, Jack E.; Munck, Allan; Sar, Madhabananda; Cidlowski, John A.

doi:10.1074/jbc.272.14.9287

Cited by 237 publications

(171 citation statements)

References 36 publications

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“…Similar analyses of GR-ER and GR-PR chimeras also suggested that cytoplasmic localization of unliganded GR is determined by its ligand binding domain (13). Second, substitution of individual and multiple phosphorylation sites in the N terminus of GR have been reported to have no effect on the localization of naive receptor to the cytoplasm of asynchronously growing COS1 cells (65). Last, the phosphorylation at these sites is highly dependent upon the cell cycle and mitogenic stimulli with the peak in phosphorylation occurring during G 2 (62, 66 -69).…”

Section: Discussionmentioning

confidence: 99%

Nucleocytoplasmic Trafficking of Steroid-free Glucocorticoid Receptor

Haché¹,

Tse²,

Reich³

et al. 1999

Journal of Biological Chemistry

118

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Glucocorticoid receptor (GR) recycles between an inactive form complexed with heat shock proteins (hsps) and localized to the cytoplasm and a free liganded form that regulates specific gene transcription in the nucleus. We report here that, contrary to previous assumptions, association of GR into hsp-containing complexes is not sufficient to prevent the shuttling or trafficking of the GR across the nuclear membrane. Following the withdrawal of treatment with cortisol or the hormone antagonist RU486, GRs recycled rapidly into hsp-associated, hormone-responsive complexes. However, cortisolwithdrawn receptors redistributed to the cytoplasm very slowly (t1 ⁄2 ‫؍‬ 8 -9 h) and RU486-withdrawn receptors not at all. Persistent localization of these GRs to the nucleus was not due to a gross defect in export, since in both instances the complexed nuclear GRs transferred efficiently between heterokaryon nuclei. Moreover, the addition of a nuclear retention signal to the N terminus of GR induced the transfer of naive receptor to the nucleus in the absence of steroid. These results suggest that the localization of GR to the cytoplasm is determined by fine control of the rates of transfer of GR across the nuclear membrane and/or by active retention that occurs independently from the association of GR with hsps.

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Section: Discussionmentioning

confidence: 99%

Nucleocytoplasmic Trafficking of Steroid-free Glucocorticoid Receptor

Haché¹,

Tse²,

Reich³

et al. 1999

Journal of Biological Chemistry

118

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“…phosphorylation greatly increased receptor half-life, suggesting that phosphorylation is involved in receptor turnover, and decreases trans-activation of a glucocorticoid-responsive simple promoter. 51 Among the kinases implied in phosphorylating GR, cyclin-dependent kinase, ERK-MAPK, and, as we discussed above, JNK 48 phosphorylate the GR in vitro at distinct serine or threonine sites that together correspond to the major phosphorylated receptor residues observed in vivo. The phosphorylation of GR by these kinases has opposite effects on transcriptional activation, so that positively (cyclindependent kinase) or negatively (ERK and JNK) regulate receptor transcriptional enhancement.…”

Section: Discussionmentioning

confidence: 99%

Glucocorticoid receptor down-Regulates c-jun amino terminal kinases induced by tumor necrosis factor ? in fetal rat hepatocyte primary cultures

et al. 1999

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The effect of dexamethasone on Jun N-terminal kinase (JNK) activity was assayed by using fetal hepatocytes in primary culture. The addition of tumor necrosis factor ␣ (TNF-␣) caused an increase in JNK in a dose-and timedependent manner. We show that activation of JNK by this extracellular signal is inhibited by dexamethasone in a dose-dependent fashion. This inhibitory effect was observed in cells treated for 10 minutes with dexamethasone in the presence of protein phosphatase inhibitors such as orthovanadate or okadaic acid, or in cells previously treated with actinomycin D. Glucocorticoid receptor (GR) can be precipitated with the fusion protein, GST-c-Jun (1-79), bound to agarose beads. However, the inhibitory effect of glucocorticoids on JNK activity was also observed using ATF-2 as substrate. In addition, dexamethasone inhibits JNK phosphorylation induced by TNF-␣. Finally, we show that GR can also be phosphorylated in tyrosine residues in response to TNF-␣ and epidermal growth factor (EGF) upon ligand-binding. Our results suggest that the antiinflammatory effect of glucocorticoids on the inflammatory pathways induced by TNF-␣ can be explained, at least in part, by modulating JNK activity through a direct proteinprotein interaction; the JNK phosphorylation and tyrosinephosphorylation state of GR may be regulatory steps also involved in that effect. (HEPATOLOGY 1999;29:849-857.)

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“…The reduction in GR protein was related temporally (Fig. 2B) and has been shown to occur at both the level of gene transcription (42,43) and post-translationally (44). Hence, the relative sensitivity of p70 S6K to regulation by glucocorticoids is related to the availability of the GR, presumably to mediate this regulation.…”

Section: Resultsmentioning

confidence: 94%

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

Shah

Iñiguez‐Lluhí

Romanelli

et al. 2002

Journal of Biological Chemistry

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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.

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Mouse Glucocorticoid Receptor Phosphorylation Status Influences Multiple Functions of the Receptor Protein

Cited by 237 publications

References 36 publications

Nucleocytoplasmic Trafficking of Steroid-free Glucocorticoid Receptor

Nucleocytoplasmic Trafficking of Steroid-free Glucocorticoid Receptor

Glucocorticoid receptor down-Regulates c-jun amino terminal kinases induced by tumor necrosis factor ? in fetal rat hepatocyte primary cultures

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

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