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p100 Deficiency Is Insufficient for Full Activation of the Alternative NF- κB Pathway: TNF Cooperates with p52- RelB in Target Gene Transcription.
- Source :
-
PLoS ONE . Aug2012, Vol. 7 Issue 8, Special section p1-12. 12p. - Publication Year :
- 2012
-
Abstract
- 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 p1002/2 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 p1 00 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 p1 00 inhibitor of the alternative NF-κB signaling pathway. [ABSTRACT FROM AUTHOR]
Details
- Language :
- English
- ISSN :
- 19326203
- Volume :
- 7
- Issue :
- 8
- Database :
- Academic Search Index
- Journal :
- PLoS ONE
- Publication Type :
- Academic Journal
- Accession number :
- 80434522
- Full Text :
- https://doi.org/10.1371/journal.pone.0042741