{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T14:12:11Z","timestamp":1791295931954,"version":"4.1.0"},"reference-count":35,"publisher":"Rockefeller University Press","issue":"1","content-domain":{"domain":["rupress.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2000,7,3]]},"abstract":"<jats:p>Glycogen synthase kinase (GSK)-3 is a protein serine\/threonine kinase that regulates differentiation and cell fate in a variety of organisms. This study examined the role of GSK-3 in antigen-specific T cell responses. Using resting T cells from P14 T cell receptor (TCR)-transgenic mice (specific for the lymphocytic choriomeningitis virus and H-2Db), we demonstrated that GSK-3\u03b2 was inactivated by serine phosphorylation after viral peptide\u2013specific stimulation in vitro. To further investigate the role of GSK-3, we have generated a retroviral vector that expresses a constitutively active form of GSK-3\u03b2 that has an alanine substitution at the regulatory amino acid, serine 9 (GSK-3\u03b2A9). Retroviral transduction of P14 TCR\u2013transgenic bone marrow stem cells, followed by reconstitution, led to the expression of GSK-3\u03b2A9 in bone marrow chimeric mice. T cells from chimeric mice demonstrate a reduction in proliferation and interleukin (IL)-2 production. In contrast, in vitro assays done in the presence of the GSK-3 inhibitor lithium led to dramatically prolonged T cell proliferation and increased IL-2 production. Furthermore, in the presence of lithium, we show that nuclear factor of activated T cells (NF-AT)c remains in the nucleus after antigen-specific stimulation of T cells. Together, these data demonstrate that GSK-3 negatively regulates the duration of T cell responses.<\/jats:p>","DOI":"10.1084\/jem.192.1.99","type":"journal-article","created":{"date-parts":[[2002,7,26]],"date-time":"2002-07-26T16:48:33Z","timestamp":1027702113000},"page":"99-104","update-policy":"https:\/\/doi.org\/10.1084\/jem.crossmarkpolicy","source":"Crossref","is-referenced-by-count":136,"title":["Negative Regulation of T Cell Proliferation and Interleukin 2 Production by the Serine Threonine Kinase Gsk-3"],"prefix":"10.1084","volume":"192","author":[{"given":"Toshiaki","family":"Ohteki","sequence":"first","affiliation":[{"name":"aOntario Cancer Institute, Department of Medical Biophysics, Toronto, Ontario M5G 2M9, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Parsons","sequence":"additional","affiliation":[{"name":"aOntario Cancer Institute, Department of Medical Biophysics, Toronto, Ontario M5G 2M9, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arsen","family":"Zakarian","sequence":"additional","affiliation":[{"name":"aOntario Cancer Institute, Department of Medical Biophysics, Toronto, Ontario M5G 2M9, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Russell G.","family":"Jones","sequence":"additional","affiliation":[{"name":"aOntario Cancer Institute, Department of Medical Biophysics, Toronto, Ontario M5G 2M9, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Linh T.","family":"Nguyen","sequence":"additional","affiliation":[{"name":"aOntario Cancer Institute, Department of Medical Biophysics, Toronto, Ontario M5G 2M9, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James R.","family":"Woodgett","sequence":"additional","affiliation":[{"name":"aOntario Cancer Institute, Department of Medical Biophysics, Toronto, Ontario M5G 2M9, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pamela S.","family":"Ohashi","sequence":"additional","affiliation":[{"name":"aOntario Cancer Institute, Department of Medical Biophysics, Toronto, Ontario M5G 2M9, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"291","published-online":{"date-parts":[[2000,7,3]]},"reference":[{"key":"2023072509195662000_R1","doi-asserted-by":"crossref","first-page":"205","DOI":"10.1016\/S0955-0674(97)80064-6","article-title":"T cell antigen receptor signal transduction","volume":"9","author":"Qian","year":"1997","journal-title":"Curr. Opin. Cell Biol."},{"key":"2023072509195662000_R2","doi-asserted-by":"crossref","first-page":"125","DOI":"10.1146\/annurev.immunol.15.1.125","article-title":"Differential signalling by lymphocyte antigen receptors","volume":"15","author":"Alberola-Ila","year":"1997","journal-title":"Annu. Rev. Immunol."},{"key":"2023072509195662000_R3","doi-asserted-by":"crossref","first-page":"707","DOI":"10.1146\/annurev.immunol.15.1.707","article-title":"Transcription factors of the NFAT familyregulation and function","volume":"15","author":"Rao","year":"1997","journal-title":"Annu. Rev. Immunol."},{"key":"2023072509195662000_R4","first-page":"269","article-title":"Regulation and functions of the glycogen synthase kinase-3 subfamily","volume":"5","author":"Woodgett","year":"1994","journal-title":"Cancer Biol."},{"key":"2023072509195662000_R5","first-page":"274","article-title":"GSK3a SHAGGY frog story","volume":"6","author":"Welsh","year":"1996","journal-title":"Cell Biol."},{"key":"2023072509195662000_R6","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1042\/bj2960015","article-title":"Inactivation of glycogen synthase kinase-3 \u03b2 by phosphorylationnew kinase connections in insulin and growth-factor signalling","volume":"296","author":"Sutherland","year":"1993","journal-title":"Biochem. J."},{"key":"2023072509195662000_R7","doi-asserted-by":"crossref","first-page":"701","DOI":"10.1042\/bj3030701","article-title":"Mitogen inactivation of glycogen synthase kinase-3\u03b2 in intact cells via serine 9 phosphorylation","volume":"303","author":"Stambolic","year":"1994","journal-title":"Biochem. J."},{"key":"2023072509195662000_R8","doi-asserted-by":"crossref","first-page":"4526","DOI":"10.1002\/j.1460-2075.1996.tb00830.x","article-title":"Wingless inactivates glycogen synthase kinase-3 via an intracellular signalling pathway which involves a protein kinase C","volume":"15","author":"Cook","year":"1996","journal-title":"EMBO (Eur. Mol. Biol. Organ.) J."},{"key":"2023072509195662000_R9","doi-asserted-by":"crossref","first-page":"1664","DOI":"10.1016\/S0960-9822(02)70790-2","article-title":"Lithium inhibits glycogen synthase kinase-3 activity and mimics Wingless signalling in intact cells","volume":"6","author":"Stambolic","year":"1996","journal-title":"Curr. Biol."},{"key":"2023072509195662000_R10","doi-asserted-by":"crossref","first-page":"725","DOI":"10.1016\/S0092-8674(00)81915-7","article-title":"Structurally related receptors and antagonists compete for secreted Wnt ligands","volume":"88","author":"Moon","year":"1997","journal-title":"Cell."},{"key":"2023072509195662000_R11","doi-asserted-by":"crossref","first-page":"1930","DOI":"10.1126\/science.275.5308.1930","article-title":"Nuclear export of NF-ATc enhanced by glycogen synthase kinase-3","volume":"275","author":"Beals","year":"1997","journal-title":"Science."},{"key":"2023072509195662000_R12","doi-asserted-by":"crossref","first-page":"11410","DOI":"10.1074\/jbc.271.19.11410","article-title":"T-cell activation leads to rapid stimulation of translation initiation factor eIF2B and inactivation of glycogen synthase kinase-3","volume":"271","author":"Welsh","year":"1996","journal-title":"J. Biol. Chem."},{"key":"2023072509195662000_R13","doi-asserted-by":"crossref","first-page":"559","DOI":"10.1038\/342559a0","article-title":"Tolerance induction in double specific T-cell receptor transgenic mice varies with antigen","volume":"342","author":"Pircher","year":"1989","journal-title":"Nature."},{"key":"2023072509195662000_R14","first-page":"136","article-title":"Versatile retroviral vectors for potential use in gene therapy","volume":"1","author":"Hawley","year":"1994","journal-title":"Gene Ther."},{"key":"2023072509195662000_R15","doi-asserted-by":"crossref","first-page":"5404","DOI":"10.4049\/jimmunol.155.11.5404","article-title":"Prevention of autoimmune disease by retroviral-mediated gene therapy","volume":"155","author":"Ally","year":"1995","journal-title":"J. Immunol."},{"key":"2023072509195662000_R16","doi-asserted-by":"crossref","first-page":"1093","DOI":"10.1084\/jem.183.3.1093","article-title":"Mature T cell reactivity altered by a peptide agonist that induces positive selection","volume":"183","author":"Sebzda","year":"1996","journal-title":"J. Exp. Med."},{"key":"2023072509195662000_R17","doi-asserted-by":"crossref","first-page":"6030","DOI":"10.4049\/jimmunol.161.11.6030","article-title":"Degree of TCR internalization and Ca2+ flux correlates with thymocyte selection","volume":"161","author":"Mariathasan","year":"1998","journal-title":"J. Immunol."},{"key":"2023072509195662000_R18","doi-asserted-by":"crossref","first-page":"3251","DOI":"10.1097\/00001756-199710200-00013","article-title":"Tau phosphorylation in transgenic mice expressing glycogen synthase kinase-3beta transgenes","volume":"8","author":"Brownlees","year":"1997","journal-title":"Neuroreport."},{"key":"2023072509195662000_R19","doi-asserted-by":"crossref","first-page":"8455","DOI":"10.1073\/pnas.93.16.8455","article-title":"A molecular mechanism for the effect of lithium on development","volume":"93","author":"Klein","year":"1996","journal-title":"Proc. Natl. Acad. Sci. USA."},{"key":"2023072509195662000_R20","doi-asserted-by":"crossref","first-page":"82","DOI":"10.1006\/dbio.1997.8552","article-title":"Activation of the Wnt signaling pathwaya molecular mechanism for lithium action","volume":"185","author":"Hedgepeth","year":"1997","journal-title":"Dev. Biol."},{"key":"2023072509195662000_R21","doi-asserted-by":"crossref","first-page":"863","DOI":"10.1083\/jcb.141.4.863","article-title":"Nucleocytoplasmic shuttling factors including Ran and CRM1 mediate nuclear export of NFAT in vitro","volume":"141","author":"Kehlenbach","year":"1998","journal-title":"J. Cell Biol."},{"key":"2023072509195662000_R22","doi-asserted-by":"crossref","first-page":"256","DOI":"10.1038\/18473","article-title":"NF-AT activation requires suppression of Crm1-dependent export by calcineurin","volume":"398","author":"Zhu","year":"1999","journal-title":"Nature."},{"key":"2023072509195662000_R23","doi-asserted-by":"crossref","first-page":"824","DOI":"10.1101\/gad.11.7.824","article-title":"Nuclear localization of NF-ATc by a calcineurin-dependent, cyclosporin-sensitive intramolecular interaction","volume":"11","author":"Beals","year":"1997","journal-title":"Genes Dev."},{"key":"2023072509195662000_R24","doi-asserted-by":"crossref","first-page":"1511","DOI":"10.1083\/jcb.145.7.1511","article-title":"The dynamics of protein kinase B regulation during B cell antigen receptor engagement","volume":"145","author":"Astoul","year":"1999","journal-title":"J. Cell Biol."},{"key":"2023072509195662000_R25","doi-asserted-by":"crossref","first-page":"233","DOI":"10.1146\/annurev.immunol.14.1.233","article-title":"CD28\/B7 system of T cell costimulation","volume":"14","author":"Lenschow","year":"1996","journal-title":"Annu. Rev. Immunol."},{"key":"2023072509195662000_R26","doi-asserted-by":"crossref","first-page":"535","DOI":"10.1126\/science.7542801","article-title":"A role for CD5 in TCR-mediated signal transduction and thymocyte selection","volume":"269","author":"Tarakhovsky","year":"1995","journal-title":"Science."},{"key":"2023072509195662000_R27","doi-asserted-by":"crossref","first-page":"2301","DOI":"10.1084\/jem.188.12.2301","article-title":"CD5 expression is developmentally regulated by T cell receptor (TCR) signals and TCR avidity","volume":"188","author":"Azzam","year":"1998","journal-title":"J. Exp. Med."},{"key":"2023072509195662000_R28","doi-asserted-by":"crossref","first-page":"901","DOI":"10.1038\/29802","article-title":"Csk controls antigen receptor-mediated development and selection of T-lineage cells","volume":"394","author":"Schmedt","year":"1998","journal-title":"Nature."},{"key":"2023072509195662000_R29","doi-asserted-by":"crossref","first-page":"1173","DOI":"10.1126\/science.272.5265.1173","article-title":"Direct regulation of ZAP-70 by SHP-1 in T cell antigen receptor signaling","volume":"272","author":"Plas","year":"1996","journal-title":"Science."},{"key":"2023072509195662000_R30","doi-asserted-by":"crossref","first-page":"839","DOI":"10.1084\/jem.184.3.839","article-title":"Signaling capacity of the T cell antigen receptor is negatively regulated by the PTP1C tyrosine phosphatase","volume":"184","author":"Pani","year":"1996","journal-title":"J. Exp. Med."},{"key":"2023072509195662000_R31","doi-asserted-by":"crossref","first-page":"9624","DOI":"10.1073\/pnas.93.18.9624","article-title":"Lack of SHPTP1 results in src-family kinase hyperactivation and thymocyte hyperresponsiveness","volume":"93","author":"Lorenz","year":"1996","journal-title":"Proc. Natl. Acad. Sci. USA."},{"key":"2023072509195662000_R32","doi-asserted-by":"crossref","first-page":"1999","DOI":"10.1093\/intimm\/11.12.1999","article-title":"The tyrosine phosphatase SHP-1 influences thymocyte selection by setting TCR signaling thresholds","volume":"11","author":"Carter","year":"1999","journal-title":"Int. Immunol."},{"key":"2023072509195662000_R33","doi-asserted-by":"crossref","first-page":"703","DOI":"10.1016\/S1074-7613(00)80575-0","article-title":"Cabin 1, a negative regulator for calcineurin signaling in T lymphocytes","volume":"8","author":"Sun","year":"1998","journal-title":"Immunity."},{"key":"2023072509195662000_R34","doi-asserted-by":"crossref","first-page":"4872","DOI":"10.1128\/MCB.18.8.4872","article-title":"Tissue hyperplasia and enhanced T-cell signalling via ZAP-70 in c-Cbl-deficient mice","volume":"18","author":"Murphy","year":"1998","journal-title":"Mol. Cell. Biol."},{"key":"2023072509195662000_R35","doi-asserted-by":"crossref","first-page":"15447","DOI":"10.1073\/pnas.95.26.15547","article-title":"Altered thymic positive selection and intracellular signals in Cbl-deficient mice","volume":"95","author":"Naramura","year":"1998","journal-title":"Proc. Natl. Acad. Sci. USA."}],"container-title":["The Journal of Experimental Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/rupress.org\/jem\/article-pdf\/192\/1\/99\/1698905\/992254.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/rupress.org\/jem\/article-pdf\/192\/1\/99\/1698905\/992254.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,7,25]],"date-time":"2023-07-25T10:35:36Z","timestamp":1690281336000},"score":1,"resource":{"primary":{"URL":"https:\/\/rupress.org\/jem\/article\/192\/1\/99\/8006\/Negative-Regulation-of-T-Cell-Proliferation-and"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2000,7,3]]},"references-count":35,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2000,7,3]]}},"URL":"https:\/\/doi.org\/10.1084\/jem.192.1.99","relation":{},"ISSN":["0022-1007","1540-9538"],"issn-type":[{"value":"0022-1007","type":"print"},{"value":"1540-9538","type":"electronic"}],"subject":[],"published":{"date-parts":[[2000,7,3]]}}}