Dataset Information

HOXA1 binds RBCK1/HOIL-1 and TRAF2 and modulates the TNF/NF-?B pathway in a transcription-independent manner.

ABSTRACT: HOX proteins define a family of key transcription factors regulating animal embryogenesis. HOX genes have also been linked to oncogenesis and HOXA1 has been described to be active in several cancers, including breast cancer. Through a proteome-wide interaction screening, we previously identified the TNFR-associated proteins RBCK1/HOIL-1 and TRAF2 as HOXA1 interactors suggesting that HOXA1 is functionally linked to the TNF/NF-?B signaling pathway. Here, we reveal a strong positive correlation between expression of HOXA1 and of members of the TNF/NF-?B pathway in breast tumor datasets. Functionally, we demonstrate that HOXA1 can activate NF-?B and operates upstream of the NF-?B inhibitor I?B. Consistently, we next demonstrate that the HOXA1-mediated activation of NF-?B is non-transcriptional and that RBCK1 and TRAF2 influences on NF-?B are epistatic to HOXA1. We also identify an 11 Histidine repeat and the homeodomain of HOXA1 to be required both for RBCK1 and TRAF2 interaction and NF-?B stimulation. Finally, we highlight that activation of NF-?B is crucial for HOXA1 oncogenic activity.

SUBMITTER: Taminiau A

PROVIDER: S-EPMC5009750 | biostudies-literature | 2016 Sep

REPOSITORIES: biostudies-literature

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HOXA1 binds RBCK1/HOIL-1 and TRAF2 and modulates the TNF/NF-κB pathway in a transcription-independent manner.

Taminiau Arnaud A Draime Amandine A Tys Janne J Lambert Barbara B Vandeputte Julie J Nguyen Nathan N Renard Patricia P Geerts Dirk D Rezsöhazy René R

Nucleic acids research 20160705 15

HOX proteins define a family of key transcription factors regulating animal embryogenesis. HOX genes have also been linked to oncogenesis and HOXA1 has been described to be active in several cancers, including breast cancer. Through a proteome-wide interaction screening, we previously identified the TNFR-associated proteins RBCK1/HOIL-1 and TRAF2 as HOXA1 interactors suggesting that HOXA1 is functionally linked to the TNF/NF-κB signaling pathway. Here, we reveal a strong positive correlation bet ...[more]

PMID: 27382069

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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

HOXA1 binds RBCK1/HOIL-1 and TRAF2 and modulates the TNF/NF-?B pathway in a transcription-independent manner.

Publications

HOXA1 binds RBCK1/HOIL-1 and TRAF2 and modulates the TNF/NF-κB pathway in a transcription-independent manner.

Similar Datasets

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