NF-kappaB-mediated up-regulation of Bcl-x and Bfl-1/A1 is required for CD40 survival signaling in B lymphocytes.
Activation of CD40 is essential for thymus-dependent humoral immune responses and rescuing B cells from apoptosis. Many of the effects of CD40 are believed to be achieved through altered gene expression. In addition to Bcl-x, a known CD40-regulated antiapoptotic molecule, we identified a related antiapoptotic molecule, A1/Bfl-1, as a CD40-inducible gene. Inhibition of the NF-kappaB pathway by overexpression of a dominant-active inhibitor of NF-kappaB abolished CD40-induced up-regulation of both the Bfl-1 and Bcl-x genes and also eliminated the ability of CD40 to rescue Fas-induced cell death. Within the upstream promoter region of Bcl-x, a potential NF-kappaB-binding sequence was found to support NF-kappaB-dependent transcriptional activation. Furthermore, expression of physiological levels of Bcl-x protected B cells from Fas-mediated apoptosis in the absence of NF-kappaB signaling. Thus, our results suggest that CD40-mediated cell survival proceeds through NF-kappaB-dependent up-regulation of Bcl-2 family members.
Lee
H H
HH
Department of Microbiology and Molecular Genetics, Jonsson Comprehensive Cancer Center, and Molecular Biology Institute, University of California, Los Angeles, CA 90095, USA.
Dadgostar
H
H
Cheng
Q
Q
Shu
J
J
Cheng
G
G
D017209:Apoptosis; D001402:B-Lymphocytes / Q000166:cytology / Q000276:immunology / Q000502:physiology*; D019013:CD40 Antigens / Q000235:genetics / Q000502:physiology*; D002460:Cell Line; D005786:Gene Expression Regulation; D006801:Humans; D016393:Lymphoma, B-Cell; D015778:Minor Histocompatibility Antigens; D016328:NF-kappa B / Q000378:metabolism*; D015345:Oligonucleotide Probes; D011401:Promoter Regions, Genetic; D011506:Proteins / Q000235:genetics*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics*; D015398:Signal Transduction; D014158:Transcription, Genetic; D014162:Transfection; D014407:Tumor Cells, Cultured; D051020:bcl-X Protein; D019014:fas Receptor / Q000502:physiology
C096816:BCL2-related protein A1; C494811:BCL2L1 protein, human; D019013:CD40 Antigens; D015778:Minor Histocompatibility Antigens; D016328:NF-kappa B; D015345:Oligonucleotide Probes; D011506:Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D051020:bcl-X Protein; D019014:fas Receptor