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Biochem J. Apr 15, 2000; 347(Pt 2): 389–397.
PMCID: PMC1220971

Among translational effectors, p70S6k is uniquely sensitive to inhibition by glucocorticoids.

Abstract

Fundamental cellular processes such as cell differentiation and growth, apoptosis and cellular metabolism are regulated differentially by glucocorticoid hormones in a cell-context-related fashion. However, these basic processes are not governed by isolated signals but are influenced by the integration of both synergistic and antagonistic extracellular and intracellular stimuli. Because glucocorticoids and insulin-like growth factor I (IGF-I) reciprocally modulate growth-regulated processes such as translation initiation, especially in skeletal muscle, a study was undertaken to address the nature of this counter-regulation. Quiescent L6 skeletal myoblasts pretreated for 4 h with the synthetic glucocorticoid dexamethasone exhibited a marked attenuation of IGF-I-induced activation of the ribosomal protein S6 kinase (p70(S6k)). The adverse effects of glucocorticoids on the activity of the endogenous enzyme were due to differential dephosphorylation at discrete residues, suggesting that, physiologically, some but not all phosphorylation sites are subject to mitogenic regulation. Furthermore, the translational repressor eIF4E-binding protein 1 (4E-BP1), which in many circumstances is co-ordinately regulated with p70(S6k), was dephosphorylated in response to glucocorticoids; however, hyperphosphorylation of the protein after stimulation with IGF-I was refractory to inhibition by glucocorticoids, as was its dissociation from its binding partner, eIF4E. Although both basal and IGF-I-stimulated rates of protein synthesis were modestly affected by glucocorticoids, the synthesis of EF1A, whose mRNA precursor is a prototype for the terminal oligopyrimidine ('TOP') transcript family and whose expression is controlled by the activity of p70(S6k), was markedly affected. Therefore in this cell system it seems that, despite the mutual control of p70(S6k) and 4E-BP1 that is often observed, p70(S6k) is more sensitive to down-regulation by glucocorticoids under growth-promoting conditions than is 4E-BP1.

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.
  • Chapman MS, Askew DJ, Kuscuoglu U, Miesfeld RL. Transcriptional control of steroid-regulated apoptosis in murine thymoma cells. Mol Endocrinol. 1996 Aug;10(8):967–978. [PubMed]
  • Dempster DW, Moonga BS, Stein LS, Horbert WR, Antakly T. Glucocorticoids inhibit bone resorption by isolated rat osteoclasts by enhancing apoptosis. J Endocrinol. 1997 Sep;154(3):397–406. [PubMed]
  • Meagher LC, Cousin JM, Seckl JR, Haslett C. Opposing effects of glucocorticoids on the rate of apoptosis in neutrophilic and eosinophilic granulocytes. J Immunol. 1996 Jun 1;156(11):4422–4428. [PubMed]
  • Miyoshi H, Ohki M, Nakagawa T, Honma Y. Glucocorticoids induce apoptosis in acute myeloid leukemia cell lines with A t(8;21) chromosome translocation. Leuk Res. 1997 Jan;21(1):45–50. [PubMed]
  • Steffen M, Scherdin U, Duvigneau C, Hölzel F. Glucocorticoid-induced alterations of morphology and growth of fibrosarcoma cells derived from 7,12-dimethylbenz(a)anthracene rat mammary tumor. Cancer Res. 1988 Dec 15;48(24 Pt 1):7212–7218. [PubMed]
  • Tchekneva E, Serafin WE. Kirsten sarcoma virus-immortalized mast cell lines. Reversible inhibition of growth by dexamethasone and evidence for the presence of an autocrine growth factor. J Immunol. 1994 Jun 15;152(12):5912–5921. [PubMed]
  • Rhee K, Bresnahan W, Hirai A, Hirai M, Thompson EA. c-Myc and cyclin D3 (CcnD3) genes are independent targets for glucocorticoid inhibition of lymphoid cell proliferation. Cancer Res. 1995 Sep 15;55(18):4188–4195. [PubMed]
  • Ramos RA, Nishio Y, Maiyar AC, Simon KE, Ridder CC, Ge Y, Firestone GL. Glucocorticoid-stimulated CCAAT/enhancer-binding protein alpha expression is required for steroid-induced G1 cell cycle arrest of minimal-deviation rat hepatoma cells. Mol Cell Biol. 1996 Oct;16(10):5288–5301. [PMC free article] [PubMed]
  • Ramalingam A, Hirai A, Thompson EA. Glucocorticoid inhibition of fibroblast proliferation and regulation of the cyclin kinase inhibitor p21Cip1. Mol Endocrinol. 1997 May;11(5):577–586. [PubMed]
  • Rogatsky I, Trowbridge JM, Garabedian MJ. Glucocorticoid receptor-mediated cell cycle arrest is achieved through distinct cell-specific transcriptional regulatory mechanisms. Mol Cell Biol. 1997 Jun;17(6):3181–3193. [PMC free article] [PubMed]
  • Rogatsky I, Hittelman AB, Pearce D, Garabedian MJ. Distinct glucocorticoid receptor transcriptional regulatory surfaces mediate the cytotoxic and cytostatic effects of glucocorticoids. Mol Cell Biol. 1999 Jul;19(7):5036–5049. [PMC free article] [PubMed]
  • Polymenis M, Schmidt EV. Coordination of cell growth with cell division. Curr Opin Genet Dev. 1999 Feb;9(1):76–80. [PubMed]
  • Brenner C, Nakayama N, Goebl M, Tanaka K, Toh-e A, Matsumoto K. CDC33 encodes mRNA cap-binding protein eIF-4E of Saccharomyces cerevisiae. Mol Cell Biol. 1988 Aug;8(8):3556–3559. [PMC free article] [PubMed]
  • Danaie P, Altmann M, Hall MN, Trachsel H, Helliwell SB. CLN3 expression is sufficient to restore G1-to-S-phase progression in Saccharomyces cerevisiae mutants defective in translation initiation factor eIF4E. Biochem J. 1999 May 15;340(Pt 1):135–141. [PMC free article] [PubMed]
  • Rosenwald IB, Rhoads DB, Callanan LD, Isselbacher KJ, Schmidt EV. Increased expression of eukaryotic translation initiation factors eIF-4E and eIF-2 alpha in response to growth induction by c-myc. Proc Natl Acad Sci U S A. 1993 Jul 1;90(13):6175–6178. [PMC free article] [PubMed]
  • Rosenwald IB, Chen JJ, Wang S, Savas L, London IM, Pullman J. Upregulation of protein synthesis initiation factor eIF-4E is an early event during colon carcinogenesis. Oncogene. 1999 Apr 15;18(15):2507–2517. [PubMed]
  • DeFatta RJ, Turbat-Herrera EA, Li BD, Anderson W, De Benedetti A. Elevated expression of eIF4E in confined early breast cancer lesions: possible role of hypoxia. Int J Cancer. 1999 Feb 9;80(4):516–522. [PubMed]
  • Wang S, Rosenwald IB, Hutzler MJ, Pihan GA, Savas L, Chen JJ, Woda BA. Expression of the eukaryotic translation initiation factors 4E and 2alpha in non-Hodgkin's lymphomas. Am J Pathol. 1999 Jul;155(1):247–255. [PMC free article] [PubMed]
  • Rousseau D, Gingras AC, Pause A, Sonenberg N. The eIF4E-binding proteins 1 and 2 are negative regulators of cell growth. Oncogene. 1996 Dec 5;13(11):2415–2420. [PubMed]
  • Lawrence JC, Jr, Fadden P, Haystead TA, Lin TA. PHAS proteins as mediators of the actions of insulin, growth factors and cAMP on protein synthesis and cell proliferation. Adv Enzyme Regul. 1997;37:239–267. [PubMed]
  • Terada N, Patel HR, Takase K, Kohno K, Nairn AC, Gelfand EW. Rapamycin selectively inhibits translation of mRNAs encoding elongation factors and ribosomal proteins. Proc Natl Acad Sci U S A. 1994 Nov 22;91(24):11477–11481. [PMC free article] [PubMed]
  • Jefferies HB, Reinhard C, Kozma SC, Thomas G. Rapamycin selectively represses translation of the "polypyrimidine tract" mRNA family. Proc Natl Acad Sci U S A. 1994 May 10;91(10):4441–4445. [PMC free article] [PubMed]
  • Jefferies HB, Fumagalli S, Dennis PB, Reinhard C, Pearson RB, Thomas G. Rapamycin suppresses 5'TOP mRNA translation through inhibition of p70s6k. EMBO J. 1997 Jun 16;16(12):3693–3704. [PMC free article] [PubMed]
  • Luo Y, Marx SO, Kiyokawa H, Koff A, Massagué J, Marks AR. Rapamycin resistance tied to defective regulation of p27Kip1. Mol Cell Biol. 1996 Dec;16(12):6744–6751. [PMC free article] [PubMed]
  • Shima H, Pende M, Chen Y, Fumagalli S, Thomas G, Kozma SC. Disruption of the p70(s6k)/p85(s6k) gene reveals a small mouse phenotype and a new functional S6 kinase. EMBO J. 1998 Nov 16;17(22):6649–6659. [PMC free article] [PubMed]
  • Shah OJ, Kimball SR, Jefferson LS. Acute attenuation of translation initiation and protein synthesis by glucocorticoids in skeletal muscle. Am J Physiol Endocrinol Metab. 2000 Jan;278(1):E76–E82. [PubMed]
  • Kimball SR, Jefferson LS. Mechanism of the inhibition of protein synthesis by vasopressin in rat liver. J Biol Chem. 1990 Oct 5;265(28):16794–16798. [PubMed]
  • Kimball SR, Karinch AM, Feldhoff RC, Mellor H, Jefferson LS. Purification and characterization of eukaryotic translational initiation factor eIF-2B from liver. Biochim Biophys Acta. 1994 Dec 15;1201(3):473–481. [PubMed]
  • Kimball SR, Horetsky RL, Jefferson LS. Signal transduction pathways involved in the regulation of protein synthesis by insulin in L6 myoblasts. Am J Physiol. 1998 Jan;274(1 Pt 1):C221–C228. [PubMed]
  • Weng QP, Andrabi K, Kozlowski MT, Grove JR, Avruch J. Multiple independent inputs are required for activation of the p70 S6 kinase. Mol Cell Biol. 1995 May;15(5):2333–2340. [PMC free article] [PubMed]
  • Weng QP, Kozlowski M, Belham C, Zhang A, Comb MJ, Avruch J. Regulation of the p70 S6 kinase by phosphorylation in vivo. Analysis using site-specific anti-phosphopeptide antibodies. J Biol Chem. 1998 Jun 26;273(26):16621–16629. [PubMed]
  • Kimball SR, Shantz LM, Horetsky RL, Jefferson LS. Leucine regulates translation of specific mRNAs in L6 myoblasts through mTOR-mediated changes in availability of eIF4E and phosphorylation of ribosomal protein S6. J Biol Chem. 1999 Apr 23;274(17):11647–11652. [PubMed]
  • Pullen N, Dennis PB, Andjelkovic M, Dufner A, Kozma SC, Hemmings BA, Thomas G. Phosphorylation and activation of p70s6k by PDK1. Science. 1998 Jan 30;279(5351):707–710. [PubMed]
  • Kobayashi T, Cohen P. Activation of serum- and glucocorticoid-regulated protein kinase by agonists that activate phosphatidylinositide 3-kinase is mediated by 3-phosphoinositide-dependent protein kinase-1 (PDK1) and PDK2. Biochem J. 1999 Apr 15;339(Pt 2):319–328. [PMC free article] [PubMed]
  • Alessi DR, James SR, Downes CP, Holmes AB, Gaffney PR, Reese CB, Cohen P. Characterization of a 3-phosphoinositide-dependent protein kinase which phosphorylates and activates protein kinase Balpha. Curr Biol. 1997 Apr 1;7(4):261–269. [PubMed]
  • Currie RA, Walker KS, Gray A, Deak M, Casamayor A, Downes CP, Cohen P, Alessi DR, Lucocq J. Role of phosphatidylinositol 3,4,5-trisphosphate in regulating the activity and localization of 3-phosphoinositide-dependent protein kinase-1. Biochem J. 1999 Feb 1;337(Pt 3):575–583. [PMC free article] [PubMed]
  • Belham C, Wu S, Avruch J. Intracellular signalling: PDK1--a kinase at the hub of things. Curr Biol. 1999 Feb 11;9(3):R93–R96. [PubMed]
  • Monfar M, Blenis J. Inhibition of p70/p85 S6 kinase activities in T cells by dexamethasone. Mol Endocrinol. 1996 Sep;10(9):1107–1115. [PubMed]
  • Sonenberg N, Gingras AC. The mRNA 5' cap-binding protein eIF4E and control of cell growth. Curr Opin Cell Biol. 1998 Apr;10(2):268–275. [PubMed]
  • Edelmann HM, Kühne C, Petritsch C, Ballou LM. Cell cycle regulation of p70 S6 kinase and p42/p44 mitogen-activated protein kinases in Swiss mouse 3T3 fibroblasts. J Biol Chem. 1996 Jan 12;271(2):963–971. [PubMed]
  • McIlroy J, Chen D, Wjasow C, Michaeli T, Backer JM. Specific activation of p85-p110 phosphatidylinositol 3'-kinase stimulates DNA synthesis by ras- and p70 S6 kinase-dependent pathways. Mol Cell Biol. 1997 Jan;17(1):248–255. [PMC free article] [PubMed]
  • Brennan P, Babbage JW, Thomas G, Cantrell D. p70(s6k) integrates phosphatidylinositol 3-kinase and rapamycin-regulated signals for E2F regulation in T lymphocytes. Mol Cell Biol. 1999 Jul;19(7):4729–4738. [PMC free article] [PubMed]
  • Montagne J, Stewart MJ, Stocker H, Hafen E, Kozma SC, Thomas G. Drosophila S6 kinase: a regulator of cell size. Science. 1999 Sep 24;285(5436):2126–2129. [PubMed]
  • Wissink S, van Heerde EC, Schmitz ML, Kalkhoven E, van der Burg B, Baeuerle PA, van der Saag PT. Distinct domains of the RelA NF-kappaB subunit are required for negative cross-talk and direct interaction with the glucocorticoid receptor. J Biol Chem. 1997 Aug 29;272(35):22278–22284. [PubMed]
  • Scheinman RI, Gualberto A, Jewell CM, Cidlowski JA, Baldwin AS., Jr Characterization of mechanisms involved in transrepression of NF-kappa B by activated glucocorticoid receptors. Mol Cell Biol. 1995 Feb;15(2):943–953. [PMC free article] [PubMed]
  • Liu W, Hillmann AG, Harmon JM. Hormone-independent repression of AP-1-inducible collagenase promoter activity by glucocorticoid receptors. Mol Cell Biol. 1995 Feb;15(2):1005–1013. [PMC free article] [PubMed]
  • Reichardt HM, Kaestner KH, Tuckermann J, Kretz O, Wessely O, Bock R, Gass P, Schmid W, Herrlich P, Angel P, et al. DNA binding of the glucocorticoid receptor is not essential for survival. Cell. 1998 May 15;93(4):531–541. [PubMed]
  • Papst PJ, Sugiyama H, Nagasawa M, Lucas JJ, Maller JL, Terada N. Cdc2-cyclin B phosphorylates p70 S6 kinase on Ser411 at mitosis. J Biol Chem. 1998 Jun 12;273(24):15077–15084. [PubMed]
  • Yaffe MB, Schutkowski M, Shen M, Zhou XZ, Stukenberg PT, Rahfeld JU, Xu J, Kuang J, Kirschner MW, Fischer G, et al. Sequence-specific and phosphorylation-dependent proline isomerization: a potential mitotic regulatory mechanism. Science. 1997 Dec 12;278(5345):1957–1960. [PubMed]
  • Gingras AC, Gygi SP, Raught B, Polakiewicz RD, Abraham RT, Hoekstra MF, Aebersold R, Sonenberg N. Regulation of 4E-BP1 phosphorylation: a novel two-step mechanism. Genes Dev. 1999 Jun 1;13(11):1422–1437. [PMC free article] [PubMed]
  • Heesom KJ, Denton RM. Dissociation of the eukaryotic initiation factor-4E/4E-BP1 complex involves phosphorylation of 4E-BP1 by an mTOR-associated kinase. FEBS Lett. 1999 Sep 3;457(3):489–493. [PubMed]
  • Isotani S, Hara K, Tokunaga C, Inoue H, Avruch J, Yonezawa K. Immunopurified mammalian target of rapamycin phosphorylates and activates p70 S6 kinase alpha in vitro. J Biol Chem. 1999 Nov 26;274(48):34493–34498. [PubMed]

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