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D3-Deficient Mice Is Compensated by Cyclin D2 in Cyclin of Normal B-1A

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D3-Deficient Mice Is Compensated by Cyclin D2 in Cyclin of Normal B-1A Disruption of Cyclin D3 Blocks Proliferation of Normal B-1a Cells, but Loss of Cyclin D3 Is Compensated by Cyclin D2 in Cyclin D3-Deficient Mice This information is current as of September 28, 2021. Jennifer M. Mataraza, Joseph R. Tumang, Maria R. Gumina, Sean M. Gurdak, Thomas L. Rothstein and Thomas C. Chiles J Immunol 2006; 177:787-795; ; doi: 10.4049/jimmunol.177.2.787 Downloaded from http://www.jimmunol.org/content/177/2/787 References This article cites 51 articles, 21 of which you can access for free at: http://www.jimmunol.org/ http://www.jimmunol.org/content/177/2/787.full#ref-list-1 Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists by guest on September 28, 2021 • Fast Publication! 4 weeks from acceptance to publication *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2006 by The American Association of Immunologists All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology Disruption of Cyclin D3 Blocks Proliferation of Normal B-1a Cells, but Loss of Cyclin D3 Is Compensated by Cyclin D2 in Cyclin D3-Deficient Mice1 Jennifer M. Mataraza,* Joseph R. Tumang,† Maria R. Gumina,* Sean M. Gurdak,† Thomas L. Rothstein,2†‡ and Thomas C. Chiles3* Peritoneal B-1a cells differ from splenic B-2 cells in the molecular mechanisms that control G0-S progression. In contrast to B-2 cells, cyclin D2 is up-regulated in a rapid and transient manner in phorbol ester (PMA)-stimulated B-1a cells, whereas cyclin D3 does not accumulate until late G1 phase. This nonoverlapping expression of cyclins D2 and D3 suggests distinct functions for these proteins in B-1a cells. To investigate the contribution of cyclin D3 in the proliferation of B-1a cells, we transduced p16INK4a peptidyl mimetics (TAT-p16) into B-1a cells before cyclin D3 induction to specifically block cyclin D3-cyclin-dependent kinase 4/6 assembly. TAT-p16 Downloaded from inhibited DNA synthesis in B-1a cells stimulated by PMA, CD40L, or LPS as well as endogenous pRb phosphorylation by cyclin D-cyclin-dependent kinase 4/6. Unexpectedly, however, cyclin D3-deficient B-1a cells proliferated in a manner similar to wild-type B-1a cells following PMA or LPS stimulation. This was due, at least in part, to the compensatory sustained accumulation of cyclin D2 throughout G0-S progression. Taken together, experiments in which cyclin D3 was inhibited in real time demonstrate the key role this cyclin plays in normal B-1a cell mitogenesis, whereas experiments with cyclin D3-deficient B-1a cells show that cyclin D2 can compensate for cyclin D3 loss in mutant mice. The Journal of Immunology, 2006, 177: 787–795. http://www.jimmunol.org/ he D-type cyclins are regulatory subunits of cyclin-de- of cyclin D-independent mechanisms to initiate mitogen-induced pendent kinase (cdk)4 4 and cdk6 (1–6). Unlike other proliferation (13–15). T cyclins whose protein levels oscillate during the cell cy- The three D-type cyclins (cyclins D1, D2, and D3) are encoded cle, accumulation of D-type cyclins is dependent on mitogenic and by separate genes that exhibit a high degree of amino acid homol- oncogenic signals (1, 2). Cyclin D-cdk4/6 complexes initiate phos- ogy and are expressed in adult tissues in a partially overlapping phorylation of the retinoblastoma tumor suppressor protein (pRb) fashion (16, 17). Mice homologous for genetic disruptions in in- and pRb-related “pocket proteins” p107 and p130; this promotes dividual D-type cyclin genes are viable and display narrow, tissue- by guest on September 28, 2021 dissociation of E2F from pRb, which reverses its G1-S inhibitory specific phenotypes, suggesting redundant function contributing to function, in part, by induction of E2F target genes (4–9). In ad- viable animals (18). Splenic B-2 lymphocytes express cyclins D2 dition, several lines of evidence point to a second noncatalytic and D3, but not cyclin D1 following BCR cross-linking (19–20). function of D-type cyclin-cdk complexes in G0-S progression by Evaluation of bone marrow and spleen from cyclin D2-deficient sequestering members of the Cip/Kip family (9). By contrast, the mice reveals normal numbers of B220ϩIgMϩ B lymphocytes (21, INK4a p16 tumor suppressor protein uniquely interacts with cdk4 22); however, the peritoneal CD5ϩ B-1 cell population is severely and cdk6, blocking cdk4/6-mediated pRb phosphorylation and diminished in cyclin D2-deficient mice (22). Cyclin D2-deficient leading to G -phase arrest (10–12). Recent analyses of mice lack- 1 B-2 cells also exhibit impaired proliferation in response to BCR ing D-type cyclins, or their catalytic partners cdk4 and cdk6, reveal cross-linking; that proliferation is not completely blocked may be that these proteins are critically required for proliferation only in due to redundancy with cyclin D3 in this tissue (23). Although selected tissues of the developing embryo, suggesting the existence little is known about the regulation and function of cyclin D3 in B cell subsets, B-2 cells deficient in c-Rel exhibit diminished cyclin *Department of Biology, Boston College, Chestnut Hill, MA 02467; †Department of D3 induction in response to BCR cross-linking (24). Interestingly, Medicine, Boston University School of Medicine, Boston, MA 02118 and Immuno- the cyclin D3 gene promoter contains multiple transcription factor biology Unit, Evans Memorial Department of Clinical Research, Boston University ␬ Medical Center, Boston, MA 02118; and ‡Department of Microbiology, Boston Uni- recognition sites, including NF- B-binding sites (25). versity School of Medicine, Boston, MA 02118 B-1 cells constitute a unique set of B lymphocytes, distinguished Received for publication December 20, 2005. Accepted for publication April from B-2 cells by numerous phenotypic and functional character- 19, 2006. istics (26–29). B-1 cells are further subdivided into CD5ϩ (B-1a) The costs of publication of this article were defrayed in part by the payment of page or CD5Ϫ (B-1b) cells and in adult mice represent the principal charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. lymphocyte population in the peritoneal cavity (26, 28, 30). B-1a 1 This work was supported by U.S. Public Health Service Grants AI-49994 (to cells are responsible for the majority of nonimmune serum IgM T.C.C.) and AI-60896 (to T.L.R.). and contribute considerable amounts of “resting” IgA (30). B-1a 2 Current address: Center for Oncology and Cell Biology, The Feinstein Institute for cells are associated with several human disease states character- Medical Research, 350 Community Drive, Manhasset, NY 11030. ized by aberrant B cell growth. In mice, monoclonal expansions of 3 Address correspondence and reprint requests to Dr. Thomas C. Chiles, Department B-1a cells that resemble human chronic lymphocytic leukemia de- of Biology, Boston College, 414 Higgins Hall, Chestnut Hill, MA 02467. E-mail address: [email protected] velop as a function of age; further, New Zealand Black mice, 4 Abbreviations used in this paper: cdk, cyclin-dependent kinase; MZ, marginal zone; which contain increased numbers of B-1a cells, develop several AML1, acute myeloid leukemia 1. types of B-1a-derived lymphoid malignancies in early life (31–33). Copyright © 2006 by The American Association of Immunologists, Inc. 0022-1767/06/$02.00 788 ROLE OF CYCLIN D3 IN B-1a CELL PROLIFERATION In adult animals, peritoneal B-1a cells are self-replenishing, giv- LT software (Verity Software House). To measure proliferation, B cells ing rise to their own progeny, following establishment early during (1–2 ϫ 104 in 0.2 ml) were cultured in quadruplicate and stimulated as ontogeny, whereas B-2 cells arise continually from surface Ig- indicated in the figure legends. DNA synthesis was measured by incubating B cells with 0.5 ␮Ci [3H]thymidine (20 Ci/mmol; New England Nuclear) negative stem cell precursors and fail to proliferate following mat- during the last6hofculture. Cells were then harvested onto glass fiber uration in the absence of exogenous stimulation (30, 34). Ex vivo filters and [3H]thymidine incorporation into DNA was quantitated by liquid B-1a cells fail to proliferate following BCR cross-linking, which scintillation spectroscopy. drives B-2 cells into S phase (35, 36). Conversely, B-1a cells enter Western blotting S phase in response to PMA and do so unusually rapidly, whereas B-2 cells require the combination of PMA and a calcium iono- B cells were solubilized in Triton X-100 buffer (20 mM Tris (pH 7.4), 100 mM NaCl, 0.1% Triton X-100) containing 2.5 ␮g/ml leupeptin/aprotinin, phore (35, 37). These results establish that B-1a cells differ from ␤ 10 mM -glycerophosphate, 1 mM PMSF, 1 mM NaF, and 1 mM Na3VO4. B-2 cells in the molecular mechanisms that control G0-S phase Insoluble debris was removed by centrifugation at 15,000 ϫ g for 15 min progression. In support of this, cyclins D2 and D3 are expressed in (4°C). Lysate protein was separated by electrophoresis through a 10% polyacrylamide SDS gel (SDS-PAGE) and transferred to an Immobilon-P a nonoverlapping manner during G0-S progression in PMA-stim- ulated B-1a cells (38, 39).
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