relA over-expression reduces tumorigenicity and activates apoptosis in human cancer cells

Ricca, Alfredo; Biroccio, Annamaria; Trisciuoglio, Daniela; Cippitelli, Marco; Zupi, Gabriella; Bufalo, Donatella Del

doi:10.1054/bjoc.2001.2174

Cited by 55 publications

(43 citation statements)

References 41 publications

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“…Third, transgenic mice that express a constitutive IkBa inhibitor, which would inhibit all Rel/NF-kB activity, in skin cells develop squamous cell carcinomas (van Hogerlinden et al, 1999). Fourth, overexpression of rela has recently been shown to decrease the tumorigenicity of a breast cancer cell line (Ricci et al, 2001). The inability of RelA mutants that are selectively Figure 4 Re-expression of RelA proteins (wild-type or C216S or S276A mutants) in rela7/7 cells.…”

Section: Discussionmentioning

confidence: 99%

Immortalized embryonic mouse fibroblasts lacking the RelA subunit of transcription factor NF-κB have a malignantly transformed phenotype

2002

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The RelA transcription factor is part of dimeric complexes, most commonly either p50-RelA (NF-kB) heterodimers or RelA homodimers, that control a variety of cellular processes. Immortalized embryonic ®broblasts established from rela knockout mice have previously been shown to be more sensitive to apoptosis induced by tumor necrosis factor (TNF) than are control ®broblasts. In this report, we show that one line of rela7/7 ®broblasts has additional phenotypes that distinguish them from control mouse ®broblasts. As compared to normal 3T3 cells, RelAde®cient ®broblasts have a spindled morphology, are less adherent to culture dishes, grow to a higher saturation density, and can form colonies in soft agar. These properties are consistent with a weakly transformed phenotype for rela7/7 cells. Furthermore, RelA-de®cient ®broblasts can form tumors in immunode®cient mice, but these tumors regress, probably because of the sensitivity of these cells to TNF. The ability of rela7/7 ®broblasts to form colonies in soft agar can be reverted by re-expression of wild-type mouse RelA, but not by expression of RelA mutants that cannot form homodimers. There is no clear correlation between the absence of RelA and the levels of expression of other Rel/NF-kB family members or adhesion proteins (ICAM-1 and VCAM-1) whose genes have upstream kB sites. Taken together, these results suggest that RelA has tumor suppressing activity under some circumstances and that RelA complexes are involved in the control of a variety of cellular properties associated with oncogenesis.

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Section: Discussionmentioning

confidence: 99%

Immortalized embryonic mouse fibroblasts lacking the RelA subunit of transcription factor NF-κB have a malignantly transformed phenotype

2002

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“…Recently, Kanno et al [33] demonstrated that the overexpression of NFkB is a pivotal event for apoptosis in HL60 cells induced by the flavonoid naringenin. It has been shown that the transcription factor NFkB participated in cell growth, differentiation, inflammatory responses induced by different signals related to the regulation of apoptosis and neoplastic transformation [34,35]. The pro-and antiapoptotic regulatory functions of NFkB have been shown to depend on the cell type, the differentiation state of the cell, and the nature of the apoptotic stimulus [35].…”

Section: Effect Of Fisetin On Mapks Phosphorylation and Nfkb Expressimentioning

confidence: 99%

Phosphoprotein levels, MAPK activities and NFκB expression are affected by fisetin

Sousa

Queiroz

Souza

et al. 2007

Journal of Enzyme Inhibition and Medicinal Chemistry

106

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Flavonoids, polyphenolic phytochemicals, are ubiquitous in plants and are commonly present in the human diet. They may exert diverse beneficial effects, including antioxidant and anticarcinogenic activities. The present study was designed to evaluate three biomolecules that play important roles in the apoptotic process: mitogen-activated protein kinases, protein phosphatases and NFkB, using HL60 cells treated with fisetin as an experimental model. Our results demonstrated that cells treated with fisetin presented high expression of NFkB, activation of MAPK p38 and an increase of phosphoprotein levels; inhibition of enzymes involved in redox status maintenance were also observed. Our findings reinforce the hypothesis that fisetin is likely to exert beneficial and/or toxic actions on cells not through its potential as antioxidant but rather through its modulation of protein kinase and phosphatase signaling cascades. Additionally, our results also indicate that the cellular effects of fisetin will ultimately depend on the cell type and on the extent to which they associate with the cells, either by interactions at the membrane or by uptake into the cytosol.

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“…8 Stimulation of the NF-kB pathway is essential for p53-mediated cell death 9 and expression of RelA alone promotes apoptosis in some cell types. 10 However, despite evidence linking NF-kB to the promotion of apoptosis, the mechanisms underlying this effect have yet to be fully resolved.…”

mentioning

confidence: 99%

Nucleolar NF-κB/RelA mediates apoptosis by causing cytoplasmic relocalization of nucleophosmin

et al. 2011

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In a number of contexts, and particularly in response to cellular stress, stimulation of the NF-kappaB (NF-jB) pathway promotes apoptosis. One mechanism underlying this pro-apoptotic activity is nucleolar sequestration of RelA, which is reported to cause cell death by repressing NF-jB-driven transcription. Here, we identify a novel and distinct nucleolar activity of RelA that induces apoptosis. We demonstrate, using a viral nucleolar localization signal (NoLS)-RelA fusion protein, that direct targeting of RelA to the nucleolus mediates apoptosis, independent of NF-jB transcriptional activity. We demonstrate a requirement for nucleophosmin (NPM, B23.1) in this apoptotic effect, and the apoptotic effect of stress-induced nucleolar RelA. We show by multiple approaches that nucleolar translocation of RelA is causally involved in the relocalization of NPM from the nucleolus to the cytoplasm and that RelA-induced cytoplasmic NPM mediates apoptosis by facilitating the mitochondrial accumulation of BAX. These data uncover a novel stress-response pathway and mechanism by which RelA promotes apoptosis, independent of its effects on NF-jB transcriptional activity. These findings are relevant to the design of novel anticancer agents that target RelA to this compartment.

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relA over-expression reduces tumorigenicity and activates apoptosis in human cancer cells

Cited by 55 publications

References 41 publications

Immortalized embryonic mouse fibroblasts lacking the RelA subunit of transcription factor NF-κB have a malignantly transformed phenotype

Immortalized embryonic mouse fibroblasts lacking the RelA subunit of transcription factor NF-κB have a malignantly transformed phenotype

Phosphoprotein levels, MAPK activities and NFκB expression are affected by fisetin

Nucleolar NF-κB/RelA mediates apoptosis by causing cytoplasmic relocalization of nucleophosmin

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