Stabilization of p53 Is a Novel Mechanism for Proapoptotic Function of NF-κB

Fujioka, Shozo; Schmidt, Christian; Sclabas, Guido M.; Li, Zhongkui; Pélicano, Hélène; Peng, Bailu; Yao, Alice C.; Niu, Jiangong; Zhang, Wei; Evans, Douglas B.; Abbruzzese, James L.; Huang, Peng; Chiao, Paul J.

doi:10.1074/jbc.m313435200

Cited by 128 publications

(95 citation statements)

References 78 publications

(54 reference statements)

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“…After 24 h of transfection, cells were fixed and stained with DAPI. Localization of p53 was monitored through red fluorescent protein, localization of IkB-DN was detected by immunofluorescent assay and nuclear DNA was visualized by DAPI staining activation (Fujioka et al, 2004). Furthermore, p53 can induce NF-kB activation via phosphorylation of RelA by ribosomal S6 kinase 1 (Bohuslav et al, 2004).…”

Section: Discussionmentioning

confidence: 99%

Epstein–Barr virus latent membrane protein 1 represses p53-mediated DNA repair and transcriptional activity

et al. 2004

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The latent membrane protein 1 (LMP1) of Epstein-Barr virus (EBV), a viral oncogene, is essential for transformation of resting B cells by the virus. We previously demonstrated that LMP1 could repress DNA repair in p53-wild-type and p53-deficient human epithelial cells. In this study, using a host cell reactivation (HCR) assay, we demonstrated that p53-enhanced DNA repair was repressed by LMP1 in p53-deficient cells. Moreover, we found that LMP1 was able to repress p53-dependent transcriptional activity. Regarding the mechanisms of p53 repression by LMP1, we found that LMP1 did not inhibit p53 function through direct interaction, by promoting protein degradation or reducing its DNA-binding ability. Using chimeric proteins in the reporter assay, we demonstrated that LMP1 inhibited p53 transactivation by influencing the N-terminal transactivation domain of p53. Subsequent experiments using various LMP1 deletion mutants indicated that a C-terminus-activating region of LMP1, CTAR1 or CTAR2, is responsible for the repression of p53-mediated DNA repair and p53-dependent transcription, which is correlated with the region responsible for NF-jB activation. Furthermore, blockage of NF-jB signalling by IjB-DN was shown to abolish the repression of p53 by LMP1, suggesting that LMP1 likely repressed p53 function through the NF-jB pathway. Based on these results, we propose that inhibition of p53-dependent transcriptional activity and DNA repair by LMP1 results in the loss of p53 activity for maintaining genomic stability, which may contribute to the oncogenesis of LMP1 in human epithelial cells.

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Section: Discussionmentioning

confidence: 99%

Epstein–Barr virus latent membrane protein 1 represses p53-mediated DNA repair and transcriptional activity

et al. 2004

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“…The suppression of NF-κB activation by SR-IκBα was found to inhibit p53-mediated apoptosis [123]. NF-κB also plays an essential role in activation of wild type p53 to initiate pro-apoptotic signaling in response to ROS accumulation [33]. This finding suggests that the inhibition of NF-κB in tumors that retain wild-type p53 may diminish, rather than augment, a therapeutic response.…”

Section: Nf-κb and The Regulation Of Apoptosismentioning

confidence: 99%

NF‐κB as a potential molecular target for cancer therapy

et al. 2007

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Abstract. Nuclear factor κB (NF-κB), a transcription factor, plays an important role in carcinogenesis as well as in the regulation of immune and inflammatory responses. NF-κB induces the expression of diverse target genes that promote cell proliferation, regulate apoptosis, facilitate angiogenesis and stimulate invasion and metastasis. Furthermore, many cancer cells show aberrant or constitutive NF-κB activation which mediates resistance to chemo-and radio-therapy. Therefore, the inhibition of NF-κB activation and its signaling pathway offers a potential cancer therapy strategy. In addition, recent studies have shown that NF-κB can also play a tumor suppressor role in certain settings. In this review, we focus on the role of NF-κB in carcinogenesis and the therapeutic potential of targeting NF-κB in cancer therapy.Keywords: NF-κB, NF-κB inhibitor, carcinogenesis, cancer therapy Structure, function and regulation of NF-κBNuclear factor-κB (NF-κB) was first identified in 1986 as a transcription factor that binds to a 10 bp DNA element in kappa immunoglobulin light-chain enhancer in B cells [128]. The mammalian NF-κB family consists of 5 members: NF-κB1 (p50/p105), NF-κB2 (p52/p100), c-Rel, RelA (p65) and RelB (Fig. 1). RelA, c-Rel and RelB are synthesized in their mature forms and contain a transactivation domain that interacts with the transcriptional apparatus. On the other hand, NF-κB1 (p50/p105) and NF-κB2 (p52/p100) are synthesized in precursor forms (p100 and p105) which contain C-terminal ankyrin repeats that are proteolysed by the proteasome resulting in the production of mature proteins (p50 and p52). Both p50 and p52 contain a DNA binding domain but lack a transactivation domain. NF-κB proteins exist in unstimulated cells as homo-or heterodimers bound to IκB proteins. Whereas RelB forms only heterodimers, all the other proteins can form both homo-and heterodimers. NF-κB proteins are characterized by the presence of a highly conserved 300 amino acid Rel homology domain that is located toward the N terminus of the protein, and which is responsible for DNA binding, dimerization, and interaction with specific inhibitory factors known as IκB proteins [7,36].

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“…Moreover, we have recently reported that BD induces apoptosis in pancreatic cancer cells by activating the phosphorylation of p38-mitogenactivated protein kinase (MAPK) (Lau et al, 2009). Although the function of ROS in the activation of p38-MAPK (Yi et al, 2004;Lee et al, 2008;Chen et al, 2009), and the regulation of NF-kB activity (Hayakawa et al, 2003;Fujioka et al, 2004), has been characterised in substances-induced apoptosis in various cancer cells, the involvement of ROS in BD-induced pancreatic cancer cell apoptosis is yet to be elucidated. Given that ROS have an important function in an array of biological responses and diverse signalling pathways, we hypothesised that BD activates pro-apoptotic pathways through the enhancement of ROS production and the inhibition of NF-kB activity in pancreatic cancer cells.…”

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confidence: 99%

Role of reactive oxygen species in brucein D-mediated p38-mitogen-activated protein kinase and nuclear factor-κB signalling pathways in human pancreatic adenocarcinoma cells

2010

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BACKGROUND: In human pancreatic adenocarcinoma, nuclear factor-kappa-B (NF-kB) transcription factor is constitutively activated that contributes to the resistance of the tumour cells to induced apoptosis. In our earlier studies, we have shown that brucein D (BD) mediated apoptosis through activation of the p38-mitogen-activated protein kinase (MAPK) signalling pathway in pancreatic cancer cells. This study investigated the function of reactive oxygen species (ROS) in BD-mediated p38-MAPK and NF-kB signalling pathways in PANC-1 cells. METHODS: Glutathione and dihydroethidium assays were used to measure the antioxidant and superoxide levels, respectively. The protein expression of p22 phox , p67 phox and p38-MAPK were examined by western blot. The NF-kB activity was evaluated by electrophoretic mobility shift assay. RESULTS: Treatment with BD depleted the intracellular glutathione levels in PANC-1 cells. Brucein D triggered the activation of NADPH oxidase isoforms, p22 phox and p67 phox while enhancing the generation of superoxide. Increases in both intracellular ROS and NADPH oxidase activity were inhibited by an antioxidant, N-acetylcysteine (NAC). Brucein D-mediated activation of p38-MAPK was also inhibited by NAC. However, inhibition of NF-kB activity in BD-treated cells was independent of ROS. In vivo studies showed that BD treatment effectively reduced the rate of xenograft human pancreatic tumour in nude mice with no significant toxicity. CONCLUSION: These data suggest that BD is an apoptogenic agent for pancreatic cancer cells through activation of the redox-sensitive p38-MAPK pathway and inhibition of NF-kB anti-apoptotic activity in pancreatic cancer cells.

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Stabilization of p53 Is a Novel Mechanism for Proapoptotic Function of NF-κB

Cited by 128 publications

References 78 publications

Epstein–Barr virus latent membrane protein 1 represses p53-mediated DNA repair and transcriptional activity

Epstein–Barr virus latent membrane protein 1 represses p53-mediated DNA repair and transcriptional activity

NF‐κB as a potential molecular target for cancer therapy

Role of reactive oxygen species in brucein D-mediated p38-mitogen-activated protein kinase and nuclear factor-κB signalling pathways in human pancreatic adenocarcinoma cells

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