title: Regulation of ribosomal RNA synthesis in T cells: requirement for GTP and Ebp1.
abstract: Mycophenolic acid (MPA) is the active metabolite of mycophenolate mofetil, an effective immunosuppressive drug. Both MPA and mycophenolate mofetil are highly specific inhibitors of guanine nucleotide synthesis and of T-cell activation. However, the mechanism by which guanine nucleotide depletion suppresses T-cell activation is unknown. Depletion of GTP inhibits ribosomal RNA synthesis in T cells by inhibiting transcription initiation factor I (TIF-IA), a GTP-binding protein that recruits RNA polymerase I to the ribosomal DNA promoter. TIF-IA-GTP binds the ErbB3-binding protein 1, and together they enhance the transcription of proliferating cell nuclear antigen (PCNA). GTP binding by TIF-IA and ErbB3-binding protein 1 phosphorylation by protein kinase C δ are both required for optimal PCNA expression. The protein kinase C inhibitor sotrastaurin markedly potentiates the inhibition of ribosomal RNA synthesis, PCNA expression, and T-cell activation induced by MPA, suggesting that the combination of the two agents are more highly effective than either alone in inducing immunosuppression.
authors.affiliation: Departments of Medicine and Chemical and Systems Biology, and.
authors.forename: Le Xuan Truong
authors.initials: le XT
authors.lastname: Nguyen
authors.affiliation: Department of Otolaryngology (Head and Neck Surgery), Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA;
authors.forename: Yunqin
authors.initials: Y
authors.lastname: Lee
authors.affiliation: Departments of Medicine and Chemical and Systems Biology, and.
authors.forename: Lenore
authors.initials: L
authors.lastname: Urbani
authors.affiliation: Division of Rheumatology, Department of Medicine, Stanford University School of Medicine, Stanford CA; and.
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Utz
authors.affiliation: Department of Pathology and Greenebaum Cancer Center, University of Maryland School of Medicine, Baltimore, MD.
authors.forename: Anne W
authors.initials: AW
authors.lastname: Hamburger
authors.affiliation: Department of Otolaryngology (Head and Neck Surgery), Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA;
authors.forename: John B
authors.initials: JB
authors.lastname: Sunwoo
authors.affiliation: Departments of Medicine and Chemical and Systems Biology, and.
authors.forename: Beverly S
authors.initials: BS
authors.lastname: Mitchell
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D015153:Blotting, Western; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D004275:DNA, Ribosomal / Q000235:genetics; D015870:Gene Expression / Q000187:drug effects; D006160:Guanosine Triphosphate / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D019169:Jurkat Cells; D053554:Keratin-20 / Q000235:genetics / Q000378:metabolism; D008213:Lymphocyte Activation / Q000187:drug effects; D009154:Mutation; D009173:Mycophenolic Acid / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D035463:Pol1 Transcription Initiation Complex Proteins / Q000235:genetics / Q000378:metabolism; D018809:Proliferating Cell Nuclear Antigen / Q000235:genetics / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding / Q000187:drug effects; D051745:Protein Kinase C-delta / Q000037:antagonists & inhibitors / Q000378:metabolism; D011758:Pyrroles / Q000494:pharmacology; D011799:Quinazolines / Q000494:pharmacology; D034622:RNA Interference; D012318:RNA Polymerase I / Q000378:metabolism; D012335:RNA, Ribosomal / Q000096:biosynthesis* / Q000235:genetics; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D013601:T-Lymphocytes / Q000187:drug effects / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D004275:DNA, Ribosomal; C507499:KRT20 protein, human; D053554:Keratin-20; C101633:PA2G4 protein, human; D035463:Pol1 Transcription Initiation Complex Proteins; D018809:Proliferating Cell Nuclear Antigen; D011758:Pyrroles; D011799:Quinazolines; D012335:RNA, Ribosomal; D016601:RNA-Binding Proteins; C428423:RRN3 protein, human; C543528:sotrastaurin; D006160:Guanosine Triphosphate; D051745:Protein Kinase C-delta; D012318:RNA Polymerase I; D009173:Mycophenolic Acid