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PMID: 10430908 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S.

NF-kappaB-mediated up-regulation of Bcl-x and Bfl-1/A1 is required for CD40 survival signaling in B lymphocytes.

Proceedings of the National Academy of Sciences of the United States of America ·Vol. 96 ·No. 16 ·1999-08-03 ·Pages 9136-41

Lee HH, Dadgostar H, Cheng Q, Shu J, Cheng G

Abstract

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.

MeSH Terms
Apoptosis B-Lymphocytes/cytology,immunology,physiology CD40 Antigens/genetics,physiology Cell Line Gene Expression Regulation Humans Lymphoma, B-Cell Minor Histocompatibility Antigens NF-kappa B/metabolism Oligonucleotide Probes Promoter Regions, Genetic Proteins/genetics Proto-Oncogene Proteins c-bcl-2/genetics Signal Transduction Transcription, Genetic Transfection Tumor Cells, Cultured bcl-X Protein fas Receptor/physiology
Chemicals
BCL2-related protein A1 BCL2L1 protein, human CD40 Antigens Minor Histocompatibility Antigens NF-kappa B Oligonucleotide Probes Proteins Proto-Oncogene Proteins c-bcl-2 bcl-X Protein fas Receptor
Authors & Affiliations
5 authors, click to expand affiliations / ORCID
Lee H H
Department of Microbiology and Molecular Genetics, Jonsson Comprehensive Cancer Center, and Molecular Biology Institute, University of California, Los Angeles, CA 90095, USA.
Dadgostar H
Cheng Q
Shu J
Cheng G
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Article Info
Journal
Proceedings of the National Academy of Sciences of the United States of America
Abbr.
Proc Natl Acad Sci U S A
ISSN
0027-8424
DOI
10.1073/pnas.96.16.9136
Published
1999-08-03
Pages
9136-41
Language
English
Region
United States
NLM ID
7505876
PMCID
PMC17745
Subset
IM
Grants
NIGMS NIH HHS · T32 GM008042 · United States
NIGMS NIH HHS · GM 08042 · United States
External Links
PubMed source DOI: 10.1073/pnas.96.16.9136 PMC Full Text View journal details
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