Cyclin D3 compensates for loss of cyclin D2 in mouse B-lymphocytes activated via the antigen receptor and CD40.
Cyclin D2 is the only D-type cyclin expressed in mature mouse B-lymphocytes, and its expression is associated with retinoblastoma protein (pRB) and pRB-related protein phosphorylation and induction of E2F activity, as B-cells enter the cell cycle following stimulation via surface IgM and/or CD40. Cyclin D-dependent kinase activity is required for cell proliferation, yet cyclin D2(-/-) mice have normal levels of mature B-lymphocytes. Here we show that B-lymphocytes from cyclin D2(-/-) mice can proliferate in response to anti-IgM and anti-CD40, but the time taken to enter S-phase is longer than for the corresponding cyclin D2(+/+) cells. This is due to the compensatory induction of cyclin D3, but not cyclin D1, which causes pRb phosphorylation on CDK4-specific sites. This is the first demonstration that loss of a D-type cyclin causes specific expression and functional compensation by another member of the family in vivo and provides a rationale for the presence of mature B-lymphocytes in cyclin D2(-/-) mice.
Lam
E W
EW
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. eric.lam@ic.ac.uk
Glassford
J
J
Banerji
L
L
Thomas
N S
NS
Sicinski
P
P
Klaus
G G
GG
D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D019013:CD40 Antigens / Q000276:immunology* / Q000378:metabolism; D002478:Cells, Cultured; D056742:Cyclin D2; D056743:Cyclin D3; D016213:Cyclins / Q000276:immunology* / Q000378:metabolism; D008213:Lymphocyte Activation; D051379:Mice; D011947:Receptors, Antigen, B-Cell / Q000276:immunology* / Q000378:metabolism
D019013:CD40 Antigens; C486196:Ccnd2 protein, mouse; C534697:Ccnd3 protein, mouse; D056742:Cyclin D2; D056743:Cyclin D3; D016213:Cyclins; D011947:Receptors, Antigen, B-Cell