Identification of New IκBα Complexes by an Iterative Experimental and Mathematical Modeling Approach

Konrath, Fabian; Witt, Johannes; Sauter, Thomas; Kulms, Dagmar

doi:10.1371/journal.pcbi.1003528

Cited by 11 publications

(11 citation statements)

References 42 publications

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“…(Ambrosi et al, 2014;Kearns and Hoffmann, 2009;O'Dea et al, 2007). In particular, it was shown that free IκB is an important regulatory target for the control of Toll signals (Konrath et al, 2014). In Drosophila, Cact partitions between free and NFκB-bound complexes.…”

Section: Results and Discussion Cact Augments Responses To High Toll mentioning

confidence: 99%

A novel function for the IκB inhibitor Cactus in promoting Dorsal nuclear localization and activity in the Drosophila embryo

et al. 2017

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The evolutionarily conserved Toll signaling pathway controls innate immunity across phyla and embryonic patterning in insects. In the embryo, Toll is required to establish gene expression domains along the dorsal-ventral axis. Pathway activation induces degradation of the IκB inhibitor Cactus, resulting in a ventral-to-dorsal nuclear gradient of the NFκB effector Dorsal. Here, we investigate how modulates Toll signals through its effects on the Dorsal gradient and on Dorsal target genes. Quantitative analysis using a series of loss- and gain-of-function conditions shows that the ventral and lateral aspects of the Dorsal gradient can behave differently with respect to Cactus fluctuations. In lateral and dorsal embryo domains, loss of Cactus allows more Dorsal to translocate to the nucleus. Unexpectedly, loss-of-function alleles decrease Dorsal nuclear localization ventrally, where Toll signals are high. Overexpression analysis suggests that this ability of Cactus to enhance Toll stems from the mobilization of a free Cactus pool induced by the Calpain A protease. These results indicate that Cactus acts to bolster Dorsal activation, in addition to its role as a NFκB inhibitor, ensuring a correct response to Toll signals.

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Section: Results and Discussion Cact Augments Responses To High Toll mentioning

confidence: 99%

A novel function for the IκB inhibitor Cactus in promoting Dorsal nuclear localization and activity in the Drosophila embryo

et al. 2017

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“…It appears that newly synthesized IκB rapidly re-associates with newly released NF-κB, thereby markedly reducing the amount of NF-κB translocated into the nucleus for the activation of cytokine genes. The activity of the NF-κB transcription factor is regulated by p-IκB through multiple intracellular signal transduction pathways (42).…”

Section: Discussionmentioning

confidence: 99%

Co-culture of hepatoma cells with hepatocytic precursor (stem-like) cells inhibits tumor cell growth and invasion by downregulating Akt/NF-κB expression

Sui

et al. 2016

Oncology Letters

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Abstract. Hepatocytic stem cells (HSCs) have inhibitory effects on hepatocarcinoma cells. The present study investigated the effects of HSC activity in hepatocarcinoma cells in vitro. A Transwell co-culture system of hepatocytic precursor (stem-like) WB-F344 cells and hepatoma CBRH-7919 cells was used to assess HSC activity in metastasized hepatoma cells in vitro. Nude mouse xenografts were used to assess HSC activity in vivo. Co-culture of hepatoma CBRH-7919 cells with WB-F344 cells suppressed the growth and colony formation, tumor cell migration and invasion capacity of CBRH-7919 cells. The nude mouse xenograft assay demonstrated that the xenograft size of CBRH-7919 cells following co-culture with WB-F344 cells was significantly smaller compared with that of control cells. Furthermore, the expression levels of the epithelial markers E-cadherin and β-catenin were downregulated, while the mesenchymal markers α-SMA and vimentin were upregulated. Co-culture of CBRH-7919 cells with WB-F344 cells downregulated NF-κB and phospho-Akt expression. In conclusion, hepatocytic precursor (stem-like) WB-F344 cells inhibited the growth, colony formation and invasion capacity of metastasized hepatoma CBRH-7919 cells in vitro and in vivo by downregulating Akt/NF-κB signaling.

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“…IL-1 causes canonical activation of NF-κB, whereas UVB activates p53. In parallel, UVB-induced inhibition of PP2Ac allows for nuclear persistence of NF-κB ( Barisic et al , 2008 ; Witt et al , 2009 ; Barisic et al , 2010 ; Zhang et al , 2011 ; Konrath et al , 2014 ) and warrants prolonged activation of p65 and CREB. The fact that NF-κB activity still vanishes at later times point can be attributed to other IκB members, such as IκBɛ, that take over NF-κB inhibition in a delayed and more linear manner ( Hoffmann et al , 2002 ).…”

Section: Discussionmentioning

confidence: 99%

Anti-Apoptotic NF-κB and “Gain of Function” mut p53 in Concert Act Pro-Apoptotic in Response to UVB+IL-1 via Enhanced TNF Production

Müller

Beissert

Kulms

2015

Journal of Investigative Dermatology

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In response to genotoxic stress, including UVB radiation, transcription factors NF-κB and p53 inevitably influence the cellular fate. Loss of p53 function has been attributed to malignant transformation and interferes with therapeutic interventions, whereas “gain of function” mutants even enhance tumor promotion. Constitutive NF-κB activation is linked to tumor maintenance and resistance against chemotherapy. The cross talk between p53 and NF-κB, however, is still under debate. Using the non-transformed keratinocyte cell line HaCaT, we shed light on the interplay between p53 and NF-κB by providing clear evidence that chronically activated NF-κB together with designated “gain of function” mutp53 promotes apoptosis via cooperative tumor necrosis factor (TNF) production in response to UVB+IL-1. Performing chromatin immunoprecipitation analysis we demonstrate that both transcription factors bind to the TNF promoter, whereas UVB-induced inhibition of Ser-Thr-phosphatase protein phosphatase 2A facilitates prolonged phosphorylation of NF-κB and the transcriptional cofactor cAMP response element–binding protein, both being required for extended TNF transcription. Thus, two major anti-apoptotic factors, NF-κB and mutp53, in concert may generate pro-apoptotic responses. As human skin is constantly exposed to UVB, causing IL-1 production as well, we hypothesize that the remarkable amount of hotspot p53 mutations within the epidermis (4%) may serve a protective function to eliminate precancerous cells at an early stage.

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Identification of New IκBα Complexes by an Iterative Experimental and Mathematical Modeling Approach

Cited by 11 publications

References 42 publications

A novel function for the IκB inhibitor Cactus in promoting Dorsal nuclear localization and activity in the Drosophila embryo

A novel function for the IκB inhibitor Cactus in promoting Dorsal nuclear localization and activity in the Drosophila embryo

Co-culture of hepatoma cells with hepatocytic precursor (stem-like) cells inhibits tumor cell growth and invasion by downregulating Akt/NF-κB expression

Anti-Apoptotic NF-κB and “Gain of Function” mut p53 in Concert Act Pro-Apoptotic in Response to UVB+IL-1 via Enhanced TNF Production

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