title: RGC-32 is a novel regulator of the T-lymphocyte cell cycle.
abstract: We have previously shown that RGC-32 is involved in cell cycle regulation in vitro. To define the in vivo role of RGC-32, we generated RGC-32 knockout mice. These mice developed normally and did not spontaneously develop overt tumors. To assess the effect of RGC-32 deficiency on cell cycle activation in T cells, we determined the proliferative rates of CD4(+) and CD8(+) T cells from the spleens of RGC-32(-/-) mice, as compared to wild-type (WT, RGC-32(+/+)) control mice. After stimulation with anti-CD3/anti-CD28, CD4(+) T cells from RGC-32(-/-) mice displayed a significant increase in [(3)H]-thymidine incorporation when compared to WT mice. In addition, both CD4(+) and CD8(+) T cells from RGC-32(-/-) mice displayed a significant increase in the proportion of proliferating Ki67(+) cells, indicating that in T cells, RGC-32 has an inhibitory effect on cell cycle activation induced by T-cell receptor/CD28 engagement. Furthermore, Akt and FOXO1 phosphorylation induced in stimulated CD4(+) T-cells from RGC-32(-/-) mice were significantly higher, indicating that RGC-32 inhibits cell cycle activation by suppressing FOXO1 activation. We also found that IL-2 mRNA and protein expression were significantly increased in RGC-32(-/-) CD4(+) T cells when compared to RGC-32(+/+) CD4(+) T cells. In addition, the effect of RGC-32 on the cell cycle and IL-2 expression was inhibited by pretreatment of the samples with LY294002, indicating a role for phosphatidylinositol 3-kinase (PI3K). Thus, RGC-32 is involved in controlling the cell cycle of T cells in vivo, and this effect is mediated by IL-2 in a PI3K-dependent fashion.
authors.affiliation: Department of Neurology, University of Maryland, School of Medicine, Baltimore, MD, USA; Research Service, Veterans Administration Maryland Health Care System, Baltimore, MD, USA.
authors.forename: Cosmin A
authors.initials: CA
authors.lastname: Tegla
authors.affiliation: Department of Neurology, University of Maryland, School of Medicine, Baltimore, MD, USA.
authors.forename: Cornelia D
authors.initials: CD
authors.lastname: Cudrici
authors.affiliation: Department of Medicine, Division of Rheumatology and Clinical Immunology, University of Maryland, School of Medicine, Baltimore, MD, USA.
authors.forename: Vinh
authors.initials: V
authors.lastname: Nguyen
authors.affiliation: Department of Neurology, University of Maryland, School of Medicine, Baltimore, MD, USA.
authors.forename: Jacob
authors.initials: J
authors.lastname: Danoff
authors.affiliation: Department of Neurology, University of Maryland, School of Medicine, Baltimore, MD, USA.
authors.forename: Adam M
authors.initials: AM
authors.lastname: Kruszewski
authors.affiliation: Department of Neurology, University of Maryland, School of Medicine, Baltimore, MD, USA.
authors.forename: Dallas
authors.initials: D
authors.lastname: Boodhoo
authors.affiliation: Department of Neurology, University of Maryland, School of Medicine, Baltimore, MD, USA.
authors.forename: Armugam P
authors.initials: AP
authors.lastname: Mekala
authors.affiliation: Department of Neurology, University of Maryland, School of Medicine, Baltimore, MD, USA; Department of Internal Medicine, "Iuliu Hatieganu" University of Medicine and Pharmacy, Cluj-Napoca, Romania.
authors.forename: Sonia I
authors.initials: SI
authors.lastname: Vlaicu
authors.affiliation: Department of Pathology, University of Maryland, School of Medicine, Baltimore, MD, USA.
authors.forename: Ching
authors.initials: C
authors.lastname: Chen
authors.affiliation: Department of Medicine, Division of Rheumatology and Clinical Immunology, University of Maryland, School of Medicine, Baltimore, MD, USA.
authors.forename: Violeta
authors.initials: V
authors.lastname: Rus
authors.affiliation: Retinal Circuit Development and Genetics Unit, N-NRL, National Eye Institute, Bethesda, MD, USA.
authors.forename: Tudor C
authors.initials: TC
authors.lastname: Badea
authors.affiliation: Department of Neurology, University of Maryland, School of Medicine, Baltimore, MD, USA; Research Service, Veterans Administration Maryland Health Care System, Baltimore, MD, USA; Veterans Administration Multiple Sclerosis Center of Excellence, Baltimore, MD, USA. Electronic address: hrus@umaryland.edu.
authors.forename: Horea
authors.initials: H
authors.lastname: Rus
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D002453:Cell Cycle; D002867:Chromones / Q000494:pharmacology; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000378:metabolism; D007376:Interleukin-2 / Q000235:genetics / Q000378:metabolism; D019394:Ki-67 Antigen / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009025:Morpholines / Q000494:pharmacology; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism
chemical_list: D002867:Chromones; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; C467200:Foxo1 protein, mouse; D007376:Interleukin-2; D019394:Ki-67 Antigen; D009025:Morpholines; D009687:Nuclear Proteins; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D012333:RNA, Messenger; C520017:Rgc-32 protein, mouse; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D051057:Proto-Oncogene Proteins c-akt
keywords: Akt; Cell cycle; IL-2; Knockout mouse; RGC-32; T-cells