Constitutive CD40 signaling in B cells selectively activates the noncanonical NF-kappaB pathway and promotes lymphomagenesis.

2.50
HDL Handle:
http://hdl.handle.net/10033/36212
Title:
Constitutive CD40 signaling in B cells selectively activates the noncanonical NF-kappaB pathway and promotes lymphomagenesis.
Authors:
Hömig-Hölzel, Cornelia; Hojer, Caroline; Rastelli, Julia; Casola, Stefano; Strobl, Lothar J; Müller, Werner; Quintanilla-Martinez, Leticia; Gewies, Andreas; Ruland, Jürgen; Rajewsky, Klaus; Zimber-Strobl, Ursula
Abstract:
CD40, a member of the tumor necrosis factor (TNF) receptor family, plays an essential role in T cell-dependent immune responses. Because CD40 is widely expressed on the surface of tumor cells in various B cell malignancies, deregulated CD40 signaling has been suggested to contribute to lymphomagenesis. In this study, we show that B cell-specific expression of a constitutively active CD40 receptor, in the form of a latent membrane protein 1 (LMP1)/CD40 chimeric protein, promoted an increase in the number of follicular and marginal zone B cells in secondary lymphoid organs in transgenic mice. The B cells displayed an activated phenotype, prolonged survival and increased proliferation, but were significantly impaired in T cell-dependent immune responses. Constitutive CD40 signaling in B cells induced selective and constitutive activation of the noncanonical NF-kappaB pathway and the mitogen-activated protein kinases Jnk and extracellular signal-regulated kinase. LMP1/CD40-expressing mice older than 12 mo developed B cell lymphomas of mono- or oligoclonal origin at high incidence, thus showing that the interplay of the signaling pathways induced by constitutive CD40 signaling is sufficient to initiate a tumorigenic process, ultimately leading to the development of B cell lymphomas.
Affiliation:
Institute of Clinical Molecular Biology and Tumor Genetics, Helmholtz Center Munich, German Research Center for Environment and Health, D-81377 Munich, Germany.
Citation:
Constitutive CD40 signaling in B cells selectively activates the noncanonical NF-kappaB pathway and promotes lymphomagenesis. 2008, 205 (6):1317-29 J. Exp. Med.
Journal:
The Journal of experimental medicine
Issue Date:
9-Jun-2008
URI:
http://hdl.handle.net/10033/36212
DOI:
10.1084/jem.20080238
PubMed ID:
18490492
Type:
Article
Language:
en
ISSN:
1540-9538
Appears in Collections:
Publications of Dept. Experimental Immunology (EI)

Full metadata record

DC FieldValueLanguage
dc.contributor.authorHömig-Hölzel, Cornelia-
dc.contributor.authorHojer, Caroline-
dc.contributor.authorRastelli, Julia-
dc.contributor.authorCasola, Stefano-
dc.contributor.authorStrobl, Lothar J-
dc.contributor.authorMüller, Werner-
dc.contributor.authorQuintanilla-Martinez, Leticia-
dc.contributor.authorGewies, Andreas-
dc.contributor.authorRuland, Jürgen-
dc.contributor.authorRajewsky, Klaus-
dc.contributor.authorZimber-Strobl, Ursula-
dc.date.accessioned2008-08-22T08:58:57Z-
dc.date.available2008-08-22T08:58:57Z-
dc.date.issued2008-06-09-
dc.identifier.citationConstitutive CD40 signaling in B cells selectively activates the noncanonical NF-kappaB pathway and promotes lymphomagenesis. 2008, 205 (6):1317-29 J. Exp. Med.en
dc.identifier.issn1540-9538-
dc.identifier.pmid18490492-
dc.identifier.doi10.1084/jem.20080238-
dc.identifier.urihttp://hdl.handle.net/10033/36212-
dc.description.abstractCD40, a member of the tumor necrosis factor (TNF) receptor family, plays an essential role in T cell-dependent immune responses. Because CD40 is widely expressed on the surface of tumor cells in various B cell malignancies, deregulated CD40 signaling has been suggested to contribute to lymphomagenesis. In this study, we show that B cell-specific expression of a constitutively active CD40 receptor, in the form of a latent membrane protein 1 (LMP1)/CD40 chimeric protein, promoted an increase in the number of follicular and marginal zone B cells in secondary lymphoid organs in transgenic mice. The B cells displayed an activated phenotype, prolonged survival and increased proliferation, but were significantly impaired in T cell-dependent immune responses. Constitutive CD40 signaling in B cells induced selective and constitutive activation of the noncanonical NF-kappaB pathway and the mitogen-activated protein kinases Jnk and extracellular signal-regulated kinase. LMP1/CD40-expressing mice older than 12 mo developed B cell lymphomas of mono- or oligoclonal origin at high incidence, thus showing that the interplay of the signaling pathways induced by constitutive CD40 signaling is sufficient to initiate a tumorigenic process, ultimately leading to the development of B cell lymphomas.en
dc.language.isoenen
dc.subject.meshAnimalsen
dc.subject.meshAntigens, CD40en
dc.subject.meshB-Lymphocytesen
dc.subject.meshCrosses, Geneticen
dc.subject.meshGerminal Centeren
dc.subject.meshLymphocyte Activationen
dc.subject.meshLymphocyte Counten
dc.subject.meshLymphomaen
dc.subject.meshLymphoma, B-Cellen
dc.subject.meshMiceen
dc.subject.meshMice, Transgenicen
dc.subject.meshNF-kappa Ben
dc.subject.meshSignal Transductionen
dc.subject.meshSpleenen
dc.subject.meshT-Lymphocytesen
dc.subject.meshTNF Receptor-Associated Factor 2en
dc.titleConstitutive CD40 signaling in B cells selectively activates the noncanonical NF-kappaB pathway and promotes lymphomagenesis.en
dc.typeArticleen
dc.contributor.departmentInstitute of Clinical Molecular Biology and Tumor Genetics, Helmholtz Center Munich, German Research Center for Environment and Health, D-81377 Munich, Germany.en
dc.identifier.journalThe Journal of experimental medicineen

Related articles on PubMed

This item is licensed under a Creative Commons License
Creative Commons
All Items in HZI are protected by copyright, with all rights reserved, unless otherwise indicated.