p100 deficiency is insufficient for full activation of the alternative NF-[kappa]B pathway: TNF cooperates with p52-RelB in target gene transcription
Background Constitutive activation of the alternative NF-κB pathway leads to marginal zone B cell expansion and disorganized spleen microarchitecture. Furthermore, uncontrolled alternative NF-κB signaling may result in the development and progression of cancer. Here, we focused on the question how d...
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| Main Authors: | , , |
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| Format: | Article (Journal) |
| Language: | English |
| Published: |
6 August 2012
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| In: |
PLOS ONE
Year: 2012, Volume: 7, Issue: 8 |
| ISSN: | 1932-6203 |
| DOI: | 10.1371/journal.pone.0042741 |
| Online Access: | Verlag, Volltext: http://dx.doi.org/10.1371/journal.pone.0042741 Verlag, Volltext: https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0042741 
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| Author Notes: | Agnes Lovas, Anja Weidemann, Daniela Albrecht, Lars Wiechert, Debra Weih, Falk Weih |
| Summary: | Background Constitutive activation of the alternative NF-κB pathway leads to marginal zone B cell expansion and disorganized spleen microarchitecture. Furthermore, uncontrolled alternative NF-κB signaling may result in the development and progression of cancer. Here, we focused on the question how does the constitutive alternative NF-κB signaling exert its effects in these malignant processes. Methodology/Principal Findings To explore the consequences of unrestricted alternative NF-κB activation on genome-wide transcription, we compared gene expression profiles of wild-type and NF-κB2/p100-deficient (p100−/−) primary mouse embryonic fibroblasts (MEFs) and spleens. Microarray experiments revealed only 73 differentially regulated genes in p100−/− vs. wild-type MEFs. Chromatin immunoprecipitation (ChIP) assays showed in p100−/− 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-κB pathways. Conclusions/Significance Our results show that p100 deficiency alone was insufficient for full induction of genes regulated by the alternative NF-κB pathway. Moreover, alternative NF-κB signaling strongly synergized both in vitro and in vivo with classical NF-κB activation, thereby extending the number of genes under the control of the p100 inhibitor of the alternative NF-κB signaling pathway. |
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| Item Description: | Gesehen am 16.10.2018 |
| Physical Description: | Online Resource |
| ISSN: | 1932-6203 |
| DOI: | 10.1371/journal.pone.0042741 |