Bim regulates BCR-induced entry of B cells into the cell cycle.
BH3-only Bcl-2 homologs are key regulators of the intrinsic apoptotic pathway. In particular, Bim, is critical for mediating apoptosis of hematopoietic cells including B cells. While studies using Bcl-2 Tg mice have defined an important role for Bcl-2 in cell cycle control, the role of BH3-only proteins is less clear. Using Bim KO mice, we show that Bim is required for B cells to enter the cell cycle normally. Bim KO B cells had reduced cell division compared to WT B cells in response to BCR, TLR3 or TLR4 signaling, whereas Bim deficiency did not affect TLR9-induced B cell division. Cell cycle progression in BCR- and LPS-stimulated Bim KO B cells was blocked at the G0-G1 stage. BCR-induced p130 degradation and pRb hyperphosphorylation on Ser807/811, which are critical for G1 entry, were reduced in Bim KO compared to WT B cells. Likewise, BCR-induced p27(Kip1) degradation was decreased in Bim KO compared to WT B cells. These defects in BCR-induced cell cycle entry correlated with a proximal defect in BCR-mediated intracellular calcium release in Bim KO B cells. Our results suggest that the balance of pro- and anti-apoptotic Bcl-2 family proteins is critical for controlling both cell cycle progression and apoptosis in B cells.
Craxton
Andrew
A
Department of Microbiology, University of Washington, Seattle, WA 98195, USA.
Draves
Kevin E
KE
Clark
Edward A
EA
D000818:Animals; D017209:Apoptosis / Q000276:immunology; D051017:Apoptosis Regulatory Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D001402:B-Lymphocytes / Q000166:cytology* / Q000276:immunology; D000072224:Bcl-2-Like Protein 11; D002453:Cell Cycle / Q000276:immunology*; D049109:Cell Proliferation; D002470:Cell Survival / Q000276:immunology; D002478:Cells, Cultured; D008565:Membrane Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011518:Proto-Oncogene Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000502:physiology; D011947:Receptors, Antigen, B-Cell / Q000502:physiology*
D051017:Apoptosis Regulatory Proteins; D000072224:Bcl-2-Like Protein 11; C000606776:Bcl2l11 protein, mouse; D008565:Membrane Proteins; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D011947:Receptors, Antigen, B-Cell