p100 Deficiency Is Insufficient for Full Activation of the Alternative NF-[kappa]B Pathway: TNF Cooperates with p52-RelB in Target Gene Transcription

Constitutive activation of the alternative NF-[kappa]B pathway leads to marginal zone B cell expansion and disorganized spleen microarchitecture. Furthermore, uncontrolled alternative NF-[kappa]B signaling may result in the development and progression of cancer. Here, we focused on the question how...

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Bibliographic Details
Published in:PloS one 2012-08, Vol.7 (8), p.e42741
Main Authors: Lovas, Agnes, Weidemann, Anja, Albrecht, Daniela, Wiechert, Lars, Weih, Debra, Weih, Falk
Format: Article
Language:English
Subjects:
Chromatin
Comparative analysis
Genes
Genetic aspects
Genomes
Genomics
Transcription (Genetics)
Tumor necrosis factor
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Summary:Constitutive activation of the alternative NF-[kappa]B pathway leads to marginal zone B cell expansion and disorganized spleen microarchitecture. Furthermore, uncontrolled alternative NF-[kappa]B signaling may result in the development and progression of cancer. Here, we focused on the question how does the constitutive alternative NF-[kappa]B signaling exert its effects in these malignant processes. To explore the consequences of unrestricted alternative NF-[kappa]B activation on genome-wide transcription, we compared gene expression profiles of wild-type and NF-[kappa]B2/p100-deficient (p100.sup.-/-) primary mouse embryonic fibroblasts (MEFs) and spleens. Microarray experiments revealed only 73 differentially regulated genes in p100.sup.-/- vs. wild-type MEFs. Chromatin immunoprecipitation (ChIP) assays showed in p100.sup.-/- MEFs direct binding of p52 and RelB to the promoter of the Enpp2 gene encoding ENPP2/Autotaxin, a protein with an important role in lymphocyte homing and cell migration. Gene ontology analysis revealed upregulation of genes with anti-apoptotic/proliferative activity (Enpp2/Atx, Serpina3g, Traf1, Rrad), chemotactic/locomotory activity (Enpp2/Atx, Ccl8), and lymphocyte homing activity (Enpp2/Atx, Cd34). Most importantly, biochemical and gene expression analyses of MEFs and spleen, respectively, indicated a marked crosstalk between classical and alternative NF-[kappa]B pathways. Our results show that p100 deficiency alone was insufficient for full induction of genes regulated by the alternative NF-[kappa]B pathway. Moreover, alternative NF-[kappa]B signaling strongly synergized both in vitro and in vivo with classical NF-[kappa]B activation, thereby extending the number of genes under the control of the p100 inhibitor of the alternative NF-[kappa]B signaling pathway.
ISSN:1932-6203
1932-6203
DOI:10.1371/journal.pone.0042741