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Cooperation of multiple signaling pathways in CD40-regulated gene expression in B lymphocytes

Dadgostar, Hajir and Zarnegar, Brian and Hoffmann, Alexander and Qin, Xiao-Feng and Truong, Uyen and Rao, Govinda and Baltimore, David and Cheng, Genhong (2002) Cooperation of multiple signaling pathways in CD40-regulated gene expression in B lymphocytes. Proceedings of the National Academy of Sciences of the United States of America, 99 (3). pp. 1497-1502. ISSN 0027-8424. http://resolver.caltech.edu/CaltechAUTHORS:DADpnas02

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Abstract

CD40/CD40L interaction is essential for multiple biological events in T dependent humoral immune responses, including B cell survival and proliferation, germinal center and memory B cell formation, and antibody isotype switching and affinity maturation. By using high-density microarrays, we examined gene expression in primary mouse B lymphocytes after multiple time points of CD40L stimulation. In addition to genes involved in cell survival and growth, which are also induced by other mitogens such as lipopolysaccharide, CD40L specifically activated genes involved in germinal center formation and T cell costimulatory molecules that facilitate T dependent humoral immunity. Next, by examining the roles of individual CD40-activated signal transduction pathways, we dissected the overall CD40-mediated response into genes independently regulated by the individual pathways or collectively by all pathways. We also found that gene down-regulation is a significant part of the overall response and that the p38 pathway plays an important role in this process, whereas the NF-kappaB pathway is important for the up-regulation of primary response genes. Our finding of overlapping independent control of gene expression modules by different pathways suggests, in principle, that distinct biological behaviors that depend on distinct gene expression subsets can be manipulated by targeting specific signaling pathways.


Item Type:Article
Additional Information:©2002 The National Academy of Sciences. Contributed by David Baltimore, December 12, 2001. We thank Drs. Gene Tanimoto, Jacques Retief, and Christina Harrington of Affymetrix for advice and for the contribution of microarrays. We thank Drs. Owen Witte, Robert Modlin, David Fruman, and Stephen Smale for critical reading of and suggestions for this manuscript. H.D. is supported by a University of California, Los Angeles, Medical Scientist Training Program training grant (GM 08042). G.C. is a Research Scholar supported by the Leukemia and Lymphoma Society of America. This work was also supported by a National Institutes of Health/National Cancer Institute research grant (CA 87924).
Subject Keywords:NF-KAPPA-B, ACTIVATED PROTEIN-KINASES, ZINC-FINGER PROTEIN, CROSS-LINKING CD40, PHOSPHOINOSITIDE 3-KINASE, ANTIGEN RECEPTOR, DENDRITIC CELLS, CYCLIN D1, LIGATION, PROLIFERATION
Record Number:CaltechAUTHORS:DADpnas02
Persistent URL:http://resolver.caltech.edu/CaltechAUTHORS:DADpnas02
Alternative URL:http://dx.doi.org/10.1073/pnas.032665099
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:577
Collection:CaltechAUTHORS
Deposited By: Tony Diaz
Deposited On:25 Aug 2005
Last Modified:26 Dec 2012 08:40

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