title: c-Rel regulation of the cell cycle in primary mouse B lymphocytes.
abstract: Surface-expressed BCR mediates the proliferation and expansion of antigen-specific B lymphocytes during a humoral immune response. Although several studies extensively characterize BCR proliferative signaling, the mechanisms linking these pathways to the cell cycle remain elusive. Using knockout mice, we show that c-Rel, a proto-oncogenic member of the NF-kappaB transcription factor family, is essential to BCR-mediated proliferation and cell cycle progression. Splenic B cells obtained from gene-targeted c-Rel knockout mice display a defective proliferation response to antigen receptor cross-linking, resulting in G(1) arrest. At the molecular level, we see that BCR stimulation of resting c-Rel(-/-) B cells fails to induce proper cyclin D3 and cyclin E expression, thereby negatively impacting G(1) phase cyclin-dependent kinase (CDK) activity. c-Rel-deficient B cells also exhibit incomplete phosphorylation of the Retinoblastoma protein (pRb) and poor expression of E2Fs, thus impeding the G(1) to S phase transition. Down-regulation of the pRb-related p130 protein during the G(0) to G(1) transition and removal of the CDK inhibitor p27(KIP1) in late G(1) parallel that of wild-type cells, suggesting that Rel-deficient B cells can exit the G(0) resting state and enter G(1) phase normally. Finally, we demonstrate that restoration of proliferation can be achieved partially upon reintroduction of cyclin E using a protein transduction method to reconstitute primary B cells. Collectively, these studies emphasize the importance of c-Rel in lymphocyte proliferation and oncogenesis, and highlight a requirement for c-Rel in establishing an effective humoral immune response.
authors.affiliation: Immunology Program, Department of Medicine, Weill Medical College of Cornell University, 515 East 71st Street, New York, NY 10021, USA.
authors.forename: Constance Y
authors.initials: CY
authors.lastname: Hsia
authors.forename: Shuhua
authors.initials: S
authors.lastname: Cheng
authors.forename: Alexander M
authors.initials: AM
authors.lastname: Owyang
authors.forename: Steven F
authors.initials: SF
authors.lastname: Dowdy
authors.forename: Hsiou-Chi
authors.initials: HC
authors.lastname: Liou
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000166:cytology* / Q000276:immunology* / Q000378:metabolism; D002453:Cell Cycle / Q000276:immunology / Q000502:physiology*; D018797:Cell Cycle Proteins / Q000378:metabolism; D002455:Cell Division; D019927:Cyclin E / Q000235:genetics; D051358:Cyclin-Dependent Kinase 4; D051361:Cyclin-Dependent Kinase 6; D050760:Cyclin-Dependent Kinase Inhibitor p27; D018844:Cyclin-Dependent Kinases / Q000378:metabolism; D016193:G1 Phase; D020573:Genes, rel; D066298:In Vitro Techniques; D008213:Lymphocyte Activation; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018448:Models, Immunological; D011518:Proto-Oncogene Proteins; D020569:Proto-Oncogene Proteins c-rel / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D016160:Retinoblastoma Protein / Q000378:metabolism; D016196:S Phase; D014158:Transcription, Genetic; D025521:Tumor Suppressor Proteins / Q000378:metabolism
chemical_list: C493961:Cdkn1b protein, mouse; D018797:Cell Cycle Proteins; D019927:Cyclin E; D011518:Proto-Oncogene Proteins; D020569:Proto-Oncogene Proteins c-rel; D016160:Retinoblastoma Protein; D025521:Tumor Suppressor Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27; C495902:Cdk4 protein, mouse; C495912:Cdk6 protein, mouse; D051358:Cyclin-Dependent Kinase 4; D051361:Cyclin-Dependent Kinase 6; D018844:Cyclin-Dependent Kinases