{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,25]],"date-time":"2026-02-25T14:15:13Z","timestamp":1772028913933,"version":"3.50.1"},"reference-count":54,"publisher":"Oxford University Press (OUP)","issue":"5","license":[{"start":{"date-parts":[[2010,3,1]],"date-time":"2010-03-01T00:00:00Z","timestamp":1267401600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2010,3,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Stem\/progenitor cells coordinate proliferation and differentiation, giving rise to appropriate cell numbers of functionally specialized cells during organogenesis. In different experimental systems, Geminin was shown to maintain progenitor cells and participate in fate determination decisions and organogenesis. Although the exact mechanisms are unclear, Geminin has been postulated to influence proliferation versus differentiation decisions. To gain insight into the in vivo role of Geminin in progenitor cell division and differentiation, we have generated mice that specifically lack Geminin in cells of lymphoid lineage through Cre-mediated recombination. T cells lacking Geminin expression upregulate early activation markers efficiently upon TCR stimulation in vitro and are able to enter the S phase of cell cycle, but show a marked defect in completing the cycle, leading to a large proportion of T cells accumulating in S\/G2\/M phases. Accordingly, T cells deficient in Geminin show a reduced ability to repopulate lymphopenic hosts in vivo. Contrary to expectations, Geminin deficiency does not alter development and differentiation of T cells in vivo. Our data suggest that Geminin is required for the proliferation events taking place either in vitro upon TCR receptor activation or during homeostatic expansion, but appears to be redundant for the proliferation and differentiation of the majority of progenitor T cell populations.<\/jats:p>","DOI":"10.4049\/jimmunol.0901983","type":"journal-article","created":{"date-parts":[[2010,1,27]],"date-time":"2010-01-27T22:19:58Z","timestamp":1264630798000},"page":"2432-2441","source":"Crossref","is-referenced-by-count":28,"title":["Differential Geminin Requirement for Proliferation of Thymocytes and Mature T Cells"],"prefix":"10.1093","volume":"184","author":[{"given":"Dimitris","family":"Karamitros","sequence":"first","affiliation":[{"name":"Department of Pharmacology"}]},{"given":"Panorea","family":"Kotantaki","sequence":"additional","affiliation":[{"name":"Department of Pharmacology"}]},{"given":"Zoi","family":"Lygerou","sequence":"additional","affiliation":[{"name":"Department of Biology, Medical School, University of Patras , Rio, Patras,","place":["Greece"]}]},{"given":"Henrique","family":"Veiga-Fernandes","sequence":"additional","affiliation":[{"name":"Division of Molecular Immunology"}]},{"given":"Vassilis","family":"Pachnis","sequence":"additional","affiliation":[{"name":"Division of Molecular Neurobiology, Medical Research Council\/National Institute for Medical Research , The Ridgeway, London,","place":["United Kingdom"]}]},{"given":"Dimitris","family":"Kioussis","sequence":"additional","affiliation":[{"name":"Division of Molecular Immunology"}]},{"given":"Stavros","family":"Taraviras","sequence":"additional","affiliation":[{"name":"Department of Pharmacology"}]}],"member":"286","published-online":{"date-parts":[[2010,3,1]]},"reference":[{"key":"2026012806324671400_r1","doi-asserted-by":"crossref","first-page":"2115","DOI":"10.2741\/1315","article-title":"DNA replication licensing.","volume":"9","author":"Nishitani","year":"2004","journal-title":"Front. Biosci."},{"key":"2026012806324671400_r2","doi-asserted-by":"crossref","first-page":"4485","DOI":"10.2741\/3018","article-title":"Cdt1 and Geminin in cancer: markers or triggers of malignant transformation?","volume":"13","author":"Petropoulou","year":"2008","journal-title":"Front. Biosci."},{"key":"2026012806324671400_r3","doi-asserted-by":"crossref","first-page":"373","DOI":"10.1016\/j.neuroscience.2007.03.050","article-title":"Licensing regulators Geminin and Cdt1 identify progenitor cells of the mouse CNS in a specific phase of the cell cycle.","volume":"147","author":"Spella","year":"2007","journal-title":"Neuroscience"},{"key":"2026012806324671400_r4","doi-asserted-by":"crossref","first-page":"1395","DOI":"10.2741\/2156","article-title":"Geminin in embryonic development: coordinating transcription and the cell cycle during differentiation.","volume":"12","author":"Kroll","year":"2007","journal-title":"Front. Biosci."},{"key":"2026012806324671400_r5","doi-asserted-by":"crossref","first-page":"3247","DOI":"10.1242\/dev.125.16.3247","article-title":"Geminin, a neuralizing molecule that demarcates the future neural plate at the onset of gastrulation.","volume":"125","author":"Kroll","year":"1998","journal-title":"Development"},{"key":"2026012806324671400_r6","doi-asserted-by":"crossref","first-page":"e2","DOI":"10.1371\/journal.pbio.0060002","article-title":"A mechanism regulating the onset of Sox2 expression in the embryonic neural plate.","volume":"6","author":"Papanayotou","year":"2008","journal-title":"PLoS Biol."},{"key":"2026012806324671400_r7","doi-asserted-by":"crossref","first-page":"2741","DOI":"10.1101\/gad.916201","article-title":"The Drosophila Geminin homolog: roles for Geminin in limiting DNA replication, in anaphase and in neurogenesis.","volume":"15","author":"Quinn","year":"2001","journal-title":"Genes Dev."},{"key":"2026012806324671400_r8","doi-asserted-by":"crossref","first-page":"745","DOI":"10.1038\/nature02292","article-title":"Direct interaction of geminin and Six3 in eye development.","volume":"427","author":"Del Bene","year":"2004","journal-title":"Nature"},{"key":"2026012806324671400_r9","doi-asserted-by":"crossref","first-page":"749","DOI":"10.1038\/nature02305","article-title":"The cell-cycle regulator geminin inhibits Hox function through direct and polycomb-mediated interactions.","volume":"427","author":"Luo","year":"2004","journal-title":"Nature"},{"key":"2026012806324671400_r10","doi-asserted-by":"crossref","first-page":"1723","DOI":"10.1101\/gad.1319105","article-title":"Geminin regulates neuronal differentiation by antagonizing Brg1 activity.","volume":"19","author":"Seo","year":"2005","journal-title":"Genes Dev."},{"key":"2026012806324671400_r11","doi-asserted-by":"crossref","first-page":"10396","DOI":"10.1073\/pnas.0800672105","article-title":"Polycomb-group complex 1 acts as an E3 ubiquitin ligase for Geminin to sustain hematopoietic stem cell activity.","volume":"105","author":"Ohtsubo","year":"2008","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2026012806324671400_r12","doi-asserted-by":"crossref","first-page":"1880","DOI":"10.1101\/gad.379706","article-title":"Geminin is essential to prevent endoreduplication and to form pluripotent cells during mammalian development.","volume":"20","author":"Gonzalez","year":"2006","journal-title":"Genes Dev."},{"key":"2026012806324671400_r13","doi-asserted-by":"crossref","first-page":"1281","DOI":"10.1111\/j.1365-2443.2006.01019.x","article-title":"Geminin is essential for the development of preimplantation mouse embryos.","volume":"11","author":"Hara","year":"2006","journal-title":"Genes Cells"},{"key":"2026012806324671400_r14","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1111\/j.0105-2896.2006.00343.x","article-title":"Regulation of T-cell progenitor survival and cell-cycle entry by the pre-T-cell receptor.","volume":"209","author":"Aifantis","year":"2006","journal-title":"Immunol. Rev."},{"key":"2026012806324671400_r15","doi-asserted-by":"crossref","first-page":"957","DOI":"10.1007\/PL00000737","article-title":"Regulation of pre-T-cell development.","volume":"57","author":"M\u00f6r\u00f6y","year":"2000","journal-title":"Cell. Mol. Life Sci."},{"key":"2026012806324671400_r16","doi-asserted-by":"crossref","first-page":"167","DOI":"10.1016\/j.coi.2004.01.011","article-title":"Lineage choices in the developing thymus: choosing the T and NKT pathways.","volume":"16","author":"Pear","year":"2004","journal-title":"Curr. Opin. Immunol."},{"key":"2026012806324671400_r17","doi-asserted-by":"crossref","first-page":"1549","DOI":"10.1084\/jem.185.9.1549","article-title":"T cell receptor (TCR)-beta gene recombination: dissociation from cell cycle regulation and developmental progression during T cell ontogeny.","volume":"185","author":"Tourigny","year":"1997","journal-title":"J. Exp. Med."},{"key":"2026012806324671400_r18","doi-asserted-by":"crossref","first-page":"4244","DOI":"10.4049\/jimmunol.150.10.4244","article-title":"A developmental pathway involving four phenotypically and functionally distinct subsets of CD3-CD4-CD8- triple-negative adult mouse thymocytes defined by CD44 and CD25 expression.","volume":"150","author":"Godfrey","year":"1993","journal-title":"J. Immunol."},{"key":"2026012806324671400_r19","doi-asserted-by":"crossref","first-page":"948","DOI":"10.1101\/gad.10.8.948","article-title":"Productive T-cell receptor beta-chain gene rearrangement: coincident regulation of cell cycle and clonality during development in vivo.","volume":"10","author":"Hoffman","year":"1996","journal-title":"Genes Dev."},{"key":"2026012806324671400_r20","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1016\/1074-7613(94)90102-3","article-title":"T cell receptor beta chain gene rearrangement and selection during thymocyte development in adult mice.","volume":"1","author":"Dudley","year":"1994","journal-title":"Immunity"},{"key":"2026012806324671400_r21","doi-asserted-by":"crossref","first-page":"62","DOI":"10.1034\/j.1600-065X.2003.00010.x","article-title":"Thymic selection revisited: how essential is it?","volume":"191","author":"von Boehmer","year":"2003","journal-title":"Immunol. Rev."},{"key":"2026012806324671400_r22","doi-asserted-by":"crossref","first-page":"547","DOI":"10.1016\/0167-5699(93)90186-O","article-title":"Control points in early T-cell development.","volume":"14","author":"Godfrey","year":"1993","journal-title":"Immunol. Today"},{"key":"2026012806324671400_r23","doi-asserted-by":"crossref","first-page":"5103","DOI":"10.4049\/jimmunol.154.10.5103","article-title":"Cell expansion and growth arrest phases during the transition from precursor (CD4-8-) to immature (CD4+8+) thymocytes in normal and genetically modified mice.","volume":"154","author":"P\u00e9nit","year":"1995","journal-title":"J. Immunol."},{"key":"2026012806324671400_r24","doi-asserted-by":"crossref","first-page":"314","DOI":"10.1002\/immu.200310005","article-title":"Transgenic mice with hematopoietic and lymphoid specific expression of Cre.","volume":"33","author":"de Boer","year":"2003","journal-title":"Eur. J. Immunol."},{"key":"2026012806324671400_r25","doi-asserted-by":"crossref","first-page":"14602","DOI":"10.1073\/pnas.94.26.14602","article-title":"Protamine-Cre recombinase transgenes efficiently recombine target sequences in the male germ line of mice, but not in embryonic stem cells.","volume":"94","author":"O\u2019Gorman","year":"1997","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2026012806324671400_r26","doi-asserted-by":"crossref","first-page":"968","DOI":"10.2144\/98256bm07","article-title":"PCR-based strategy for genotyping mice and ES cells harboring loxP sites.","volume":"25","author":"Mantamadiotis","year":"1998","journal-title":"Biotechniques"},{"key":"2026012806324671400_r27","doi-asserted-by":"crossref","first-page":"2761","DOI":"10.4049\/jimmunol.162.5.2761","article-title":"Dissecting NK cell development using a novel alymphoid mouse model: investigating the role of the c-abl proto-oncogene in murine NK cell differentiation.","volume":"162","author":"Colucci","year":"1999","journal-title":"J. Immunol."},{"key":"2026012806324671400_r28","doi-asserted-by":"crossref","first-page":"3368","DOI":"10.1111\/j.1432-1033.2004.04271.x","article-title":"Cdt1 and geminin are down-regulated upon cell cycle exit and are over-expressed in cancer-derived cell lines.","volume":"271","author":"Xouri","year":"2004","journal-title":"Eur. J. Biochem."},{"key":"2026012806324671400_r29","doi-asserted-by":"crossref","first-page":"979","DOI":"10.1016\/0092-8674(89)90631-4","article-title":"Human CD2 3\u2032-flanking sequences confer high-level, T cell-specific, position-independent gene expression in transgenic mice.","volume":"56","author":"Greaves","year":"1989","journal-title":"Cell"},{"key":"2026012806324671400_r30","doi-asserted-by":"crossref","first-page":"1127","DOI":"10.1084\/jem.179.4.1127","article-title":"Turnover of naive- and memory-phenotype T cells.","volume":"179","author":"Tough","year":"1994","journal-title":"J. Exp. Med."},{"key":"2026012806324671400_r31","doi-asserted-by":"crossref","first-page":"389","DOI":"10.1038\/nri821","article-title":"CD4+ CD25+ suppressor T cells: more questions than answers.","volume":"2","author":"Shevach","year":"2002","journal-title":"Nat. Rev. Immunol."},{"key":"2026012806324671400_r32","doi-asserted-by":"crossref","first-page":"644","DOI":"10.1016\/S0952-7915(01)00273-4","article-title":"CD4(+) regulatory T cells.","volume":"13","author":"Read","year":"2001","journal-title":"Curr. Opin. Immunol."},{"key":"2026012806324671400_r33","doi-asserted-by":"crossref","first-page":"F9","DOI":"10.1084\/jem.192.4.F9","article-title":"Homeostatic T cell proliferation: how far can T cells be activated to self-ligands?","volume":"192","author":"Surh","year":"2000","journal-title":"J. Exp. Med."},{"key":"2026012806324671400_r34","doi-asserted-by":"crossref","first-page":"547","DOI":"10.1038\/nri853","article-title":"Maintaining the norm: T-cell homeostasis.","volume":"2","author":"Jameson","year":"2002","journal-title":"Nat. Rev. Immunol."},{"key":"2026012806324671400_r35","doi-asserted-by":"crossref","first-page":"1379","DOI":"10.4049\/jimmunol.139.5.1379","article-title":"The stable and permanent expansion of functional T lymphocytes in athymic nude rats after a single injection of mature T cells.","volume":"139","author":"Bell","year":"1987","journal-title":"J. Immunol."},{"key":"2026012806324671400_r36","doi-asserted-by":"crossref","first-page":"40","DOI":"10.1016\/j.cellimm.2008.01.003","article-title":"Quantitative analysis of T cell homeostatic proliferation.","volume":"250","author":"Li","year":"2007","journal-title":"Cell. Immunol."},{"key":"2026012806324671400_r37","doi-asserted-by":"crossref","first-page":"30854","DOI":"10.1074\/jbc.C300251200","article-title":"The SCF(Skp2) ubiquitin ligase complex interacts with the human replication licensing factor Cdt1 and regulates Cdt1 degradation.","volume":"278","author":"Li","year":"2003","journal-title":"J. Biol. Chem."},{"key":"2026012806324671400_r38","doi-asserted-by":"crossref","first-page":"23416","DOI":"10.1074\/jbc.M501208200","article-title":"Degradation of Cdt1 during S phase is Skp2-independent and is required for efficient progression of mammalian cells through S phase.","volume":"280","author":"Takeda","year":"2005","journal-title":"J. Biol. Chem."},{"key":"2026012806324671400_r39","doi-asserted-by":"crossref","first-page":"1126","DOI":"10.1038\/sj.emboj.7601002","article-title":"Two E3 ubiquitin ligases, SCF-Skp2 and DDB1-Cul4, target human Cdt1 for proteolysis.","volume":"25","author":"Nishitani","year":"2006","journal-title":"EMBO J."},{"key":"2026012806324671400_r40","doi-asserted-by":"crossref","first-page":"1043","DOI":"10.1016\/S0092-8674(00)81209-X","article-title":"Geminin, an inhibitor of DNA replication, is degraded during mitosis.","volume":"93","author":"McGarry","year":"1998","journal-title":"Cell"},{"key":"2026012806324671400_r41","doi-asserted-by":"crossref","first-page":"44905","DOI":"10.1074\/jbc.M105406200","article-title":"The human licensing factor for DNA replication Cdt1 accumulates in G1 and is destabilized after initiation of S-phase.","volume":"276","author":"Nishitani","year":"2001","journal-title":"J. Biol. Chem."},{"key":"2026012806324671400_r42","doi-asserted-by":"crossref","first-page":"412","DOI":"10.1016\/S0006-291X(03)00773-3","article-title":"Expression and phosphorylation of the replication regulator protein geminin.","volume":"305","author":"Kulartz","year":"2003","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"2026012806324671400_r43","doi-asserted-by":"crossref","first-page":"3662","DOI":"10.1091\/mbc.e02-04-0199","article-title":"Geminin deficiency causes a Chk1-dependent G2 arrest in Xenopus.","volume":"13","author":"McGarry","year":"2002","journal-title":"Mol. Biol. Cell"},{"key":"2026012806324671400_r44","doi-asserted-by":"crossref","first-page":"1052","DOI":"10.1038\/sj.embor.7400527","article-title":"Depletion of licensing inhibitor geminin causes centrosome overduplication and mitotic defects.","volume":"6","author":"Tachibana","year":"2005","journal-title":"EMBO Rep."},{"key":"2026012806324671400_r45","doi-asserted-by":"crossref","first-page":"1868","DOI":"10.1128\/MCB.22.6.1868-1880.2002","article-title":"Control of DNA replication and chromosome ploidy by geminin and cyclin A.","volume":"22","author":"Mihaylov","year":"2002","journal-title":"Mol. Cell. Biol."},{"key":"2026012806324671400_r46","doi-asserted-by":"crossref","first-page":"473","DOI":"10.1083\/jcb.200403106","article-title":"Loss of Geminin induces rereplication in the presence of functional p53.","volume":"165","author":"Melixetian","year":"2004","journal-title":"J. Cell Biol."},{"key":"2026012806324671400_r47","doi-asserted-by":"crossref","first-page":"7140","DOI":"10.1128\/MCB.24.16.7140-7150.2004","article-title":"Rereplication by depletion of geminin is seen regardless of p53 status and activates a G2\/M checkpoint.","volume":"24","author":"Zhu","year":"2004","journal-title":"Mol. Cell. Biol."},{"key":"2026012806324671400_r48","doi-asserted-by":"crossref","first-page":"184","DOI":"10.1101\/gad.1495007","article-title":"The APC\/C inhibitor, Emi1, is essential for prevention of rereplication.","volume":"21","author":"Machida","year":"2007","journal-title":"Genes Dev."},{"key":"2026012806324671400_r49","doi-asserted-by":"crossref","first-page":"30807","DOI":"10.1074\/jbc.M312644200","article-title":"Proteolysis of DNA replication licensing factor Cdt1 in S-phase is performed independently of geminin through its N-terminal region.","volume":"279","author":"Nishitani","year":"2004","journal-title":"J. Biol. Chem."},{"key":"2026012806324671400_r50","first-page":"3","article-title":"The generation and fate of thymocytes.","volume":"2","author":"Shortman","year":"1990","journal-title":"Semin. Immunol."},{"key":"2026012806324671400_r51","doi-asserted-by":"crossref","first-page":"1184","DOI":"10.1242\/jcs.041889","article-title":"Redundant and differential regulation of multiple licensing factors ensures prevention of re-replication in normal human cells.","volume":"122","author":"Sugimoto","year":"2009","journal-title":"J. Cell Sci."},{"key":"2026012806324671400_r52","doi-asserted-by":"crossref","first-page":"4469","DOI":"10.1038\/sj.onc.1210243","article-title":"Cell-specific responses to loss of cyclin-dependent kinases.","volume":"26","author":"Berthet","year":"2007","journal-title":"Oncogene"},{"key":"2026012806324671400_r53","doi-asserted-by":"crossref","first-page":"30","DOI":"10.1111\/j.1469-7580.2008.00931.x","article-title":"G1 to S phase cell cycle transition in somatic and embryonic stem cells.","volume":"213","author":"Neganova","year":"2008","journal-title":"J. Anat."},{"key":"2026012806324671400_r54","doi-asserted-by":"crossref","first-page":"20","DOI":"10.1038\/onc.2008.358","article-title":"Expression and functional analysis of G1 to S regulatory components reveals an important role for CDK2 in cell cycle regulation in human embryonic stem cells.","volume":"28","author":"Neganova","year":"2008","journal-title":"Oncogene"}],"container-title":["The Journal of Immunology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/jimmunol\/article-pdf\/184\/5\/2432\/62719100\/ji_0901983.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/jimmunol\/article-pdf\/184\/5\/2432\/62719100\/ji_0901983.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,1,28]],"date-time":"2026-01-28T11:36:37Z","timestamp":1769600197000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/jimmunol\/article\/184\/5\/2432\/8007255"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2010,3,1]]},"references-count":54,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2010,3,1]]},"published-print":{"date-parts":[[2010,3,1]]}},"URL":"https:\/\/doi.org\/10.4049\/jimmunol.0901983","relation":{},"ISSN":["1550-6606","0022-1767"],"issn-type":[{"value":"1550-6606","type":"electronic"},{"value":"0022-1767","type":"print"}],"subject":[],"published-other":{"date-parts":[[2010,3]]},"published":{"date-parts":[[2010,3,1]]}}}