Cross talk between stimulated NF-κB and the tumor suppressor p53

Schneider, Günter; Henrich, Annika; Greiner, Georg; Wolf, V.; Lovas, Ágnes; Wieczorek, Martin; Wagner, Tobias; Reichardt, Sigrid; Werder, Alexander von; Schmid, Roland M.; Weih, Falk; Heinzel, Thorsten; Saur, Dieter; Krämer, Oliver H.

doi:10.1038/onc.2010.46

Cited by 144 publications

(133 citation statements)

References 80 publications

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“…R175H has previously been shown to reprogramme the cellular transcriptome through recruitment to novel target genes by various transcription factors such as NF-Y (Di Agostino et al, 2006), VDR (Stambolsky et al, 2010) and nuclear factor-kb (Schneider et al, 2010). Indeed, our pathway analysis also showed that the nuclear factor-kb-signalling pathway was strongly upregulated upon induced expression of p53-R175H (Supplementary Figure S5B), further confirming a role for nuclear factor-kb in the GOF of mutant p53 (Weisz et al, 2007).…”

Section: Input Igg Pab1620supporting

confidence: 78%

Mutant p53 drives multinucleation and invasion through a process that is suppressed by ANKRD11

et al. 2011

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Mutations of p53 in cancer can result in a gain of function associated with tumour progression and metastasis. We show that inducible expression of several p53 'hotspot' mutants promote a range of centrosome abnormalities, including centrosome amplification, increased centrosome size and loss of cohesion, which lead to mitotic defects and multinucleation. These mutant p53-expressing cells also show a change in morphology and enhanced invasive capabilities. Consequently, we sought for a means to specifically target the function of mutant p53 in cancer cells. This study has identified ANKRD11 as a key regulator of the oncogenic potential of mutant p53. Loss of ANKRD11 expression with p53 mutation defines breast cancer patients with poor prognosis. ANKRD11 alleviates the mitotic defects driven by mutant p53 and suppresses mutant p53-mediated mesenchymal-like transformation and invasion. Mechanistically, we show that ANKRD11 restores a native conformation to the mutant p53 protein and causes dissociation of the mutant p53-p63 complex. This represents the first evidence of an endogenous protein with the capacity to suppress the oncogenic properties of mutant p53.

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Section: Input Igg Pab1620supporting

confidence: 78%

Mutant p53 drives multinucleation and invasion through a process that is suppressed by ANKRD11

et al. 2011

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“…Avidin-biotin complex DNA (ABCD) assays were carried out as described (38,39). Proteins recognized by specific antibodies were detected with Western blots generated with X-ray films.…”

Section: Avidin-biotin Complex Dna Analysismentioning

confidence: 99%

Leflunomide Induces Apoptosis in Fludarabine-Resistant and Clinically Refractory CLL Cells

Dietrich

Krämer

Hahn

et al. 2012

Clinical Cancer Research

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Purpose: Environmental conditions in lymph node proliferation centers protect chronic lymphocytic leukemia (CLL) cells from apoptotic triggers. This situation can be mimicked by in vitro stimulation with CD40 ligand (CD40L) and interleukin 4 (IL-4). Our study investigates the impact of the drug leflunomide to overcome apoptosis resistance of CLL cells.Experimental Design: CLL cells were stimulated with CD40L and IL-4 and treated with fludarabine and the leflunomide metabolite A771726.Results: Resistance to fludarabine-mediated apoptosis was induced by CD40 activation alone stimulating high levels of BCL-XL and MCL1 protein expression. Apoptosis resistance was further enhanced by a complementary Janus-activated kinase (JAK)/STAT signal induced by IL-4. In contrast, CLL proliferation required both a CD40 and a JAK/STAT signal and could be completely blocked by pan-JAK inhibition. Leflunomide (A771726) antagonized CD40L/IL-4-induced proliferation at very low concentrations (3 mg/ mL) reported to inhibit dihydroorotate dehydrogenase. At a concentration of 10 mg/mL, A771726 additionally attenuated STAT3/6 phosphorylation, whereas apoptosis of CD40L/IL-4-activated ("resistant") CLL cells was achieved with higher concentrations (IC 50 : 80 mg/mL). Apoptosis was also effectively induced by A771726 in clinically refractory CLL cells with and without a defective p53 pathway. Induction of apoptosis involved inhibition of NF-kB activity and loss of BCL-XL and MCL1 expression. In combination with fludarabine, A771726 synergistically induced apoptosis (IC 50 : 56 mg/mL).Conclusion: We thus show that A771726 overcomes CD40L/IL-4-mediated resistance to fludarabine in CLL cells of untreated as well as clinically refractory CLL cells. We present a possible novel therapeutic principle for attacking chemoresistant CLL cells. Clin Cancer Res; 18(2); 417-31. Ó2011 AACR.

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“…Whole-cell lysates were prepared and western blots and immunoprecipitations were carried out as recently described (Fritsche et al, 2009;Schneider et al, 2010;Schneider et al, 2006). Nuclear extracts were prepared as described (Häussler et al, 2005).…”

Section: Western Blotting and Immunoprecipitationmentioning

confidence: 99%

“…Chromatin immunoprecipitation (ChIP) assays were performed as recently described (Fritsche et al, 2009;Schneider et al, 2010;Schneider et al, 2006). An equal amount of chromatin (50-100 g) was used for each precipitation.…”

Section: Chromatin Immunoprecipitation Assaysmentioning

confidence: 99%

IKKα controls canonical TGFβ–SMAD signaling to regulate genes expressing SNAIL and SLUG during EMT in Panc1 cells

Brandl

Seidler

Haller

et al. 2010

Journal of Cell Science

116

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There was an error published in J. Cell Sci. 123, 4231-4239.In Fig. 4A, the cRel siRNA western blot panel was inadvertently constructed using the wrong images and all three western blots showed incorrect loading controls. The correct images and loading controls are shown in the figure below. The mistake in the figure did not affect the conclusions of the paper.We apologise for this mistake. . TGFb-dependent downregulation of E-cadherin is NFkB-independent. (A) Panc1 cells were transfected with a control or RelA/p65-, RelB-or c-Relspecific siRNA. At 24 hours after the transfection, cells were treated with 10 ng/ml TGFb or were left as an untreated control in DMEM without FCS. After an additional 48 hours, western blots detected RelA/p65, RelB or c-Rel and E-cadherin expression. The membrane was stripped and probed for a-tubulin or b-actin to ensure equal protein loading. (B) Panc1 (upper graph) and MDA-MB231 cells (lower graph) cells were co-transfected with a control or IKKa-specific siRNA and 500 ng of the pGL3control-, NFkB-or SMAD-luciferase reporter gene constructs as indicated. At 24 hours after the transfection, cells were treated with 10 ng/ml TGFb or were left as an untreated control. Luciferase activity was measured 6 hours after the TGFb treatment (Student's t-test: *P,0.05 versus control). (C) Panc1 (upper graph) and MDA-MB231 (lower graph) cells were transfected with a control or IKKa-specific siRNA. At 48 hours after the transfection, cells were stimulated with TGFb (10 ng/ml) for 20 minutes and binding of SMAD3 and SMAD4 to a SMAD consensus oligonucleotide was detected using ABCD assays. Input represents 5% of whole-cell extract of control siRNA-transfected cells. (D) Panc1 cells were treated as in C. Immunoprecipitation was performed with an IKKa-specific antibody or pre-immune serum as a control. Western blots of immunoprecipitates were probed with antibodies against IKKa and SMAD3. Input represents 5% of whole-cell extract of control siRNA-transfected Panc1 cells. (E) MDA-MB231 cells were transfected with a control or IKKa-specific siRNA. At 24 hours after the transfection, cells were treated with 10 ng/ml TGFb or were left as an untreated control in DMEM without FCS. After an additional 48 hours, western blots detected IKKa expression. The membrane was stripped and probed for b-actin to ensure equal protein loading.

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Cross talk between stimulated NF-κB and the tumor suppressor p53

Cited by 144 publications

References 80 publications

Mutant p53 drives multinucleation and invasion through a process that is suppressed by ANKRD11

Mutant p53 drives multinucleation and invasion through a process that is suppressed by ANKRD11

Leflunomide Induces Apoptosis in Fludarabine-Resistant and Clinically Refractory CLL Cells

IKKα controls canonical TGFβ–SMAD signaling to regulate genes expressing SNAIL and SLUG during EMT in Panc1 cells

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