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P100 Deficiency is insufficient for full activation of the alternative NF-?B pathway: TNF cooperates with p52-RelB in target gene transcription.

ABSTRACT: BACKGROUND: Constitutive activation of the alternative NF-?B pathway leads to marginal zone B cell expansion and disorganized spleen microarchitecture. Furthermore, uncontrolled alternative NF-?B signaling may result in the development and progression of cancer. Here, we focused on the question how does the constitutive alternative NF-?B signaling exert its effects in these malignant processes. METHODOLOGY/PRINCIPAL FINDINGS: To explore the consequences of unrestricted alternative NF-?B activation on genome-wide transcription, we compared gene expression profiles of wild-type and NF-?B2/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-?B pathways. CONCLUSIONS/SIGNIFICANCE: Our results show that p100 deficiency alone was insufficient for full induction of genes regulated by the alternative NF-?B pathway. Moreover, alternative NF-?B signaling strongly synergized both in vitro and in vivo with classical NF-?B activation, thereby extending the number of genes under the control of the p100 inhibitor of the alternative NF-?B signaling pathway.

SUBMITTER: Lovas A

PROVIDER: S-EPMC3412832 | biostudies-literature | 2012

REPOSITORIES: biostudies-literature

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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.

Lovas Agnes A Weidemann Anja A Albrecht Daniela D Wiechert Lars L Weih Debra D Weih Falk F

PloS one 20120806 8

<h4>Background</h4>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.<h4>Methodology/principal findings</h4>To explore the consequences of unrestricted alternative N ...[more]

PMID: 22880094

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Project description:Tumor necrosis factor (TNF) is a pleiotropic cytokine whose primary physiological function involves coordinating inflammatory and adaptive immune responses. However, uncontrolled TNF signaling causes aberrant inflammation and has been implicated in several human ailments. Therefore, an understanding of the molecular mechanisms underlying dynamical and gene controls of TNF signaling bear significance for human health. As such, TNF engages the canonical nuclear factor kappa B (NF-κB) pathway to activate RelA:p50 heterodimers, which induce expression of specific immune response genes. Brief and chronic TNF stimulation produces transient and long-lasting NF-κB activities, respectively. Negative feedback regulators of the canonical pathway, including IκBα, are thought to ensure transient RelA:p50 responses to short-lived TNF signals. The non-canonical NF-κB pathway mediates RelB activity during immune differentiation involving p100. We uncovered an unexpected role of p100 in TNF signaling. Brief TNF stimulation of p100-deficient cells triggered an additional late NF-κB activity consisting of RelB:p50 heterodimers, which modified the TNF-induced gene-expression program. In p100-deficient cells subjected to brief TNF stimulation, RelB:p50 not only sustained the expression of a subset of RelA-target immune response genes but also activated additional genes that were not normally induced by TNF in WT mouse embryonic fibroblasts (MEFs) and were related to immune differentiation and metabolic processes. Despite this RelB-mediated distinct gene control, however, RelA and RelB bound to mostly overlapping chromatin sites in p100-deficient cells. Repeated TNF pulses strengthened this RelB:p50 activity, which was supported by NF-κB-driven RelB synthesis. Finally, brief TNF stimulation elicited late-acting expressions of NF-κB target pro-survival genes in p100-deficient myeloma cells. In sum, our study suggests that the immune-differentiation regulator p100 enforces specificity of TNF signaling and that varied p100 levels may provide for modifying TNF responses in diverse physiological and pathological settings.

Dataset Information

P100 Deficiency is insufficient for full activation of the alternative NF-?B pathway: TNF cooperates with p52-RelB in target gene transcription.

Publications

p100 Deficiency is insufficient for full activation of the alternative NF-κB pathway: TNF cooperates with p52-RelB in target gene transcription.

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