Vav is required for cyclin D2 induction and proliferation of mouse B lymphocytes activated via the antigen Receptor.
B lymphocytes from mice null for the Rho-family guanine-nucleotide exchange factor, Vav, are defective in their ability to proliferate in response to BCR cross-linking, but are able to proliferate normally in response to LPS. In addition, they have a depletion of CD5(+) (B1) lymphocytes and defective IgG class switching. This phenotype is reminiscent of that observed in mice null for the cell cycle regulatory protein, cyclin D2. We demonstrate here that the inability of vav(-/-) B cells to proliferate in response to BCR ligation is due to an inability to induce cyclin D2. In addition, we show that the proliferative defect of these cells occurs after the cells have entered early G1 phase. Analyses of potential down-stream signaling intermediates revealed differential activation of the stress-activated MAP kinases in the absence of Vav, normal activation of the ERK, MAPK, and phosphatidylinositol 3-kinase pathways, and defective intracellular calcium mobilization. We further demonstrate that intracellular calcium homeostasis is required for cyclin D2 induction, implicating a possible link with the defective calcium response of vav(-/-) B cells and their inability to induce cyclin D2.
Glassford
J
J
Ludwig Institute for Cancer Research and Section of Virology and Cell Biology, Imperial College School of Medicine at St Mary's, Norfolk Place, London W2 1PG, United Kingdom.
Holman
M
M
Banerji
L
L
Clayton
E
E
Klaus
G G
GG
Turner
M
M
Lam
E W
EW
D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology*; D002118:Calcium / Q000378:metabolism; D002453:Cell Cycle / Q000502:physiology; D018797:Cell Cycle Proteins / Q000378:metabolism; D002455:Cell Division / Q000502:physiology*; D056742:Cyclin D2; D016213:Cyclins / Q000096:biosynthesis*; D007075:Immunoglobulin M / Q000276:immunology; D008070:Lipopolysaccharides / Q000494:pharmacology; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D015513:Oncogene Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D051567:Proto-Oncogene Proteins c-vav; D011947:Receptors, Antigen, B-Cell / Q000502:physiology*; D015398:Signal Transduction; D048051:p38 Mitogen-Activated Protein Kinases
C486196:Ccnd2 protein, mouse; D018797:Cell Cycle Proteins; D056742:Cyclin D2; D016213:Cyclins; D007075:Immunoglobulin M; D008070:Lipopolysaccharides; D015513:Oncogene Proteins; D051567:Proto-Oncogene Proteins c-vav; D011947:Receptors, Antigen, B-Cell; C496619:Vav1 protein, mouse; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D002118:Calcium