title: Bcl-xL protein protects from C/EBP homologous protein (CHOP)-dependent apoptosis during plasma cell differentiation.
abstract: Although it is known that the unfolded protein response (UPR) plays a significant role in the process of plasma cell differentiation, the contribution of the individual sensors of the UPR to this process remains unclear. In this study we examine the death signals and compensatory survival signals activated during B cell activation and the first stages of plasma cell differentiation. During in vitro differentiation of both primary murine B cells and the Bcl1 cell line, we demonstrate that in addition to activation of the physiological UPR, changes in the expression of several Bcl-2 proteins occur, which are consistent with a lowering of the apoptotic threshold of the cell. Specifically, we observed decreased expression of Bcl-2 and Mcl-1 and increased expression of the proapoptotic protein Bim. However, these changes were countered by Bcl-xL induction, which is necessary to protect differentiating cells both from ER stress-induced death by tunicamycin and from the death signals inherent in differentiation. Consistent with differentiating cells becoming dependent on Bcl-xL for survival, the addition of ABT-737 resulted in apoptosis in differentiating cells through the inhibition of sequestration of Bim. Confirming this result, differentiation in the context of RNAi-mediated Bcl-xL knockdown also induced apoptosis. This cell death is C/EBP homologous protein (CHOP)-dependent, connecting these events to the UPR. Thus plasma cell differentiation proceeds through a Bcl-xL-dependent intermediate.
authors.affiliation: From the Departments of Hematology and Medical Oncology, Cell Biology and Winship Cancer Institute, and.
authors.forename: Brian T
authors.initials: BT
authors.lastname: Gaudette
authors.affiliation: the Department of Surgery and Emory Transplant Center, Emory University, Atlanta, Georgia 30322.
authors.forename: Neal N
authors.initials: NN
authors.lastname: Iwakoshi
authors.affiliation: From the Departments of Hematology and Medical Oncology, Cell Biology and Winship Cancer Institute, and lboise@emory.edu.
authors.forename: Lawrence H
authors.initials: LH
authors.lastname: Boise
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D001483:Base Sequence; D001713:Biphenyl Compounds / Q000494:pharmacology; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology*; D002460:Cell Line; D017931:DNA Primers; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D020868:Gene Silencing; D015848:Interleukin-5 / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D009596:Nitrophenols / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology; D010950:Plasma Cells / Q000166:cytology*; D013449:Sulfonamides / Q000494:pharmacology; D051742:Transcription Factor CHOP / Q000502:physiology*; D056811:Unfolded Protein Response; D051020:bcl-X Protein / Q000235:genetics / Q000502:physiology*
chemical_list: C501332:ABT-737; C494812:Bcl2l1 protein, mouse; D001713:Biphenyl Compounds; D017931:DNA Primers; C497250:Ddit3 protein, mouse; D015848:Interleukin-5; D008070:Lipopolysaccharides; D009596:Nitrophenols; D010879:Piperazines; D013449:Sulfonamides; D051020:bcl-X Protein; D051742:Transcription Factor CHOP
keywords: Apoptosis; Bcl-2 Proteins; Differentiation; ER Stress; Lymphocyte; Plasma Cell; UPR