Cyclin D2 controls B cell progenitor numbers.
Cyclin D2 affects B cell proliferation and differentiation in vivo. It is rate-limiting for B cell receptor (BCR)-dependent proliferation of B cells, and cyclin D2-/- mice lack CD5+(B1) B lymphocytes. We show here that the bone marrow (BM) of cyclin D2-/- mice contains half the numbers of Sca1+B220+ B cell progenitors but normal levels of Sca1+ progenitor cells of other lineages. In addition, clonal analysis of BM from the cyclin D2-/- and cyclin D2+/+ mice confirmed that there were fewer B cell progenitors (B220+) in the cyclin D2-/- mice. In addition, the colonies from cyclin D2-/- mice were less mature (CD19lo) than those from cyclin D2+/+ mice (CD19Hi). The number of mature B2 B cells in vivo is the same in cyclin D2-/- and cyclin D2+/+ animals. Lack of cyclin D2 protein may be compensated by cyclin D3, as cyclin-dependent kinase (cdk)6 coimmunoprecipitates with cyclin D3 but not cyclin D1 from BM mononuclear cells of cyclin D2-/- mice. It is active, as endogenous retinoblastoma protein is phosphorylated at the cdk6/4-cyclin D-specific sites, S807/811. We conclude that cyclin D2 is rate-limiting for the production of B lymphoid progenitor cells whose proliferation does not depend on BCR signaling.
Mohamedali
Azim
A
Leukaemia Sciences, Guy's, King's, St. Thomas' School of Medicine, Rayne Institute, 123 Coldharbour Lane, London SE5 9RS, UK. nicholas.s.thomas@kcl.ac.uk
Soeiro
Inês
I
Lea
Nicholas C
NC
Glassford
Janet
J
Banerji
Lolita
L
Mufti
Ghulam J
GJ
Lam
Eric W-F
EW
Thomas
N Shaun B
NS
D000818:Animals; D018941:Antigens, CD19 / Q000378:metabolism; D000943:Antigens, Differentiation / Q000378:metabolism; D001402:B-Lymphocytes / Q000166:cytology* / Q000187:drug effects; D015153:Blotting, Western; D001853:Bone Marrow / Q000378:metabolism; D018956:CD5 Antigens / Q000032:analysis / Q000378:metabolism; D002452:Cell Count; D002478:Cells, Cultured; D003114:Colony-Forming Units Assay; D056742:Cyclin D2; D056743:Cyclin D3; D016213:Cyclins / Q000378:metabolism / Q000502:physiology*; D006412:Hematopoietic Stem Cells / Q000166:cytology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D015513:Oncogene Proteins / Q000378:metabolism; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases; D011518:Proto-Oncogene Proteins; D051562:Proto-Oncogene Proteins c-bcr; D016160:Retinoblastoma Protein / Q000378:metabolism; D015398:Signal Transduction
D018941:Antigens, CD19; D000943:Antigens, Differentiation; D018956:CD5 Antigens; C486196:Ccnd2 protein, mouse; C534697:Ccnd3 protein, mouse; D056742:Cyclin D2; D056743:Cyclin D3; D016213:Cyclins; D015513:Oncogene Proteins; D011518:Proto-Oncogene Proteins; D016160:Retinoblastoma Protein; C047076:senescent cell differentiation antigen; D011505:Protein-Tyrosine Kinases; C496614:Bcr protein, mouse; D051562:Proto-Oncogene Proteins c-bcr