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Structural characterization of the ternary complex that mediates termination of NF-?B signaling by I?B?.

ABSTRACT: The transcription factor NF-?B is used in many systems for the transduction of extracellular signals into the expression of signal-responsive genes. Published structural data explain the activation of NF-?B through degradation of its dedicated inhibitor I?B?, but the mechanism by which NF-?B-mediated signaling is turned off by its removal from the DNA in the presence of newly synthesized I?B? (termed stripping) is unknown. Previous kinetic studies showed that I?B? accelerates NF-?B dissociation from DNA, and a transient ternary complex between NF-?B, its cognate DNA sequence, and I?B? was observed. Here we structurally characterize the >100-kDa ternary complex by NMR and negative stain EM and show a modeled structure that is consistent with the measurements. These data provide a structural basis for previously unidentified insights into the molecular mechanism of stripping.

SUBMITTER: Mukherjee SP

PROVIDER: S-EPMC4896678 | biostudies-literature | 2016 May

REPOSITORIES: biostudies-literature

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Structural characterization of the ternary complex that mediates termination of NF-κB signaling by IκBα.

Mukherjee Sulakshana P SP Quintas Pedro O PO McNulty Reginald R Komives Elizabeth A EA Dyson H Jane HJ

Proceedings of the National Academy of Sciences of the United States of America 20160516 22

The transcription factor NF-κB is used in many systems for the transduction of extracellular signals into the expression of signal-responsive genes. Published structural data explain the activation of NF-κB through degradation of its dedicated inhibitor IκBα, but the mechanism by which NF-κB-mediated signaling is turned off by its removal from the DNA in the presence of newly synthesized IκBα (termed stripping) is unknown. Previous kinetic studies showed that IκBα accelerates NF-κB dissociation ...[more]

PMID: 27185953

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Project description:BackgroundRegulator of cullins 1 (ROC1) is an important catalytic subunit of cullin-RING E3 ligase. Nuclear factor-kappa B (NF-κB) signaling is closely related to tumor invasion and metastasis. Earlier, we reported that ROC1 was associated with a poor prognosis in patients with bladder cancer (BCa). However, it is unclear whether ROC1 is involved in the NF-κB signaling associated with malignant BCa progression.MethodsThe expression of ROC1 and p65 in bladder cancer and paracancerous tissues were detected by immunohistochemistry (IHC). Pearson correlation was used to assess correlation between ROC1 and p65 protein expressions. The wound-healing and transwell assays were used to monitor cell invasion and migration. The effect of ROC1 on the expression of key proteins in the NF-κB signaling was determined by immunofluorescence and western blot (WB). Cycloheximide (CHX), MG132 and immunoprecipitation assays were used to evaluate the effect of ROC1 on the ubiquitination of phosphorylated inhibitor of kappa B alpha (p-IκBα). A lung metastasis mouse model was generated to detect the role of ROC1 in tumor metastasis.ResultsWe found that ROC1 was up-regulated in BCa tissues and cell lines, and high ROC1 levels were positively correlated with higher tumour grade, lymph node metastasis, distant metastasis and poor prognosis. Linear-regression analysis showed significant a Pearson correlation between ROC1 and nuclear p65 expression in BCa tissue microarray (TMA) samples. Functional studies demonstrated that ROC1 promoted BCa cell invasion and migration. In vitro and in vivo experiments showed that ROC1 activated NF-κB signaling by enhancing the ubiquitination of p-IκBα, which caused p65 nuclear translocation and promoted the transcription of some metastasis-related target genes, such as urokinase-type plasminogen activator receptor (uPAR), intracellular adhesion molecule 1 (ICAM1), vascular cell adhesion molecule 1 (VCAM1), and matrix metalloproteinase 9 (MMP9), resulting in promoting BCa metastasis.ConclusionROC1 plays an important role in the progression of BCa and serves as a potential diagnostic and therapeutic target for patients with BCa.

Dataset Information

Structural characterization of the ternary complex that mediates termination of NF-?B signaling by I?B?.

Publications

Structural characterization of the ternary complex that mediates termination of NF-κB signaling by IκBα.

Similar Datasets

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