Control of apoptosis by Rel/NF-κB transcription factors

Barkett, Margaret; Gilmore, Thomas D.

doi:10.1038/sj.onc.1203238

Cited by 1,143 publications

(915 citation statements)

References 202 publications

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“…11 Higher activity of NF-kB is a common characteristic of many tumor cells. 1,2,12,13 HuT-78, a cutaneous lymphoid T cell line that constitutively expresses NF-kB, is resistant to TNFinduced apoptosis. 14,15 Constitutive activity of IKK, mediated by different factors like interleukin-1, epidermal growth factor, heregulin, and so on, has been shown in constitutive NF-kBexpressing cells.…”

mentioning

confidence: 99%

“…19 NF-kB, possibly through the activation of the antiapoptotic genes, plays a key role in the protection of cells against inducers of apoptosis including chemotherapeutic drugs. 13 Several mechanisms including increased expression of NF-kB proteins, mutations and/or deletions in IkBa gene, and increased IkBa turnover, and so on, are involved in NF-kB activation in tumor cells. 1,20 In spite of the growing evidence of the important role of NF-kB in tumorigenesis and its resistance to chemotherapy, only few attempts have been made to understand the mechanisms of the constitutive activity of NF-kB in tumor cells and its regulation for successful therapy.…”

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confidence: 99%

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Inhibition of RelA phosphorylation sensitizes apoptosis in constitutive NF-kappaB-expressing and chemoresistant cells

Manna

Sarkar

2006

Cell Death Differ

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The compound 5-(4-methoxyarylimino)-2-N-(3,4-dichlorophenyl)-3-oxo-1,2,4-thiadiazolidine (P 3 -25) is known to possess antibacterial, anti-fungal, anti-tubercular, and local anesthetic activities. We studied the anti-tumorigenic activity of P 3 -25 and the role of nuclear transcription factor kappaB (NF-jB) in this process. In constitutive NF-jB-expressing cells, treatment with P 3 -25 inhibited the expression of NF-jB-dependent reporter gene, adhesion molecules, and cyclooxygenase. It downregulated phosphorylation of p65 by inhibiting upstream kinases, such as protein kinase A and casein kinase II, but did not alter NF-jB DNA-binding activity. Alone, P 3 -25 induced apoptosis in NF-jB-expressing and doxorubicin-resistant breast cancer cells, and in the presence of other chemotherapeutic agents, it potentiated apoptosis. Overall, our results suggest that P 3 -25 exerts antitumorigenic activity by inhibiting phosphorylation of p65, the transcriptionally active subunit of NF-jB by inhibiting its upstream kinases, and potentiates apoptosis mediated by chemotherapeutic agents. These results suggest novel approaches for designing of anticancer drugs for combination chemotherapy.

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confidence: 99%

mentioning

confidence: 99%

Inhibition of RelA phosphorylation sensitizes apoptosis in constitutive NF-kappaB-expressing and chemoresistant cells

Manna

Sarkar

2006

Cell Death Differ

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“…Also, this report is the first to describe a method to reliably measure NF-kB activation in archival tumour tissue. Important NF-kB target genes in cancer comprise antiapoptotic genes (Barkett and Gilmore, 1999), genes involved in angiogenesis (Aggarwal, 2004), and genes involved in the determination of invasiveness and the potential to metastasise (Fujioka et al, 2003a, b). Consequently, NF-kB inhibition by transfection with a mutated IkBa leads to a repression of tumorigenic potential (Fujioka et al, 2003b), angiogenesis (Xiong et al, 2004) and metastatic potential (Fujioka et al, 2003a) of pancreatic adenocarcinoma cell lines in xenograft mouse models.…”

Section: Shuklamentioning

confidence: 99%

High expression of RelA/p65 is associated with activation of nuclear factor-κB-dependent signaling in pancreatic cancer and marks a patient population with poor prognosis

et al. 2007

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Activation of nuclear factor-kB (NF-kB) signaling was observed in pancreatic adenocarcinoma cell lines and tumours. However, information on the expression of RelA/p65, the major transcription activating NF-kB subunit, in these carcinomas and possible correlations thereof with NF-kB activation and patient survival is not available. To provide this missing translational link, we analysed expression of RelA/p65 in 82 pancreatic adenocarcinomas by immunohistochemistry. Moreover, we measured activation of the NF-kB pathway in 11 tumours by quantitative PCR for NF-kB target genes. We observed strong cytoplasmic or nuclear expression of RelA/p65 in 42 and 37 carcinomas, respectively. High cytoplasmic and nuclear expression of RelA/p65 had negative prognostic impact with 2-year survival rates for patients without cytoplasmic or nuclear RelA/p65 positivity of 41 and 40% and rates for patients with strong cytoplasmic or nuclear RelA/p65 expression of 22 and 20%, respectively. High RelA/p65 expression was correlated to increased expression of NF-kB target genes. The observation that high expression of RelA/p65 is correlated to an activation of the NF-kB pathway and indicates poor patient survival identifies a patient subgroup that might particularly benefit from NF-kB-inhibiting agents in the treatment of pancreatic cancer. Based on our findings, this subgroup could be identified by applying simple immunohistochemical techniques.

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“…ATM phosphorylates IKKγ, the regulatory subunit of the IκB kinase IKK, which activates the transcription factor NF-κB (see below). Like p53, NF-κB promotes apoptosis in response to genotoxic stress (Barkett and Gilmore, 1999). A third transcription factor, E2F1, is also a substrate for ATM (Shiloh, 2006).…”

Section: Dna Damage Responsementioning

confidence: 99%

“…NF-κB is generally thought of as a survival factor, inhibiting apoptosis, driving cell proliferation and regulating differentiation. However, in response to genotoxic stress, activation of NF-κB promotes apoptosis (Barkett and Gilmore, 1999). NF-κB is activated by a variety of different types of genotoxic stress (Janssens and Tschopp, 2006).…”

Section: Nf-κbmentioning

confidence: 99%

Signaling mechanisms involved in the response to genotoxic stress and regulating lifespan

Niedernhofer

Robbins

2008

The International Journal of Biochemistry & Cell Biology

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Ageing is defined by the loss of functional reserve over time, leading to a decreased capacity to maintain homeostasis under stress and increased risk of morbidity and mortality. Ageing is extremely heterogeneous between individuals and even between tissues within an organism, making it challenging to identify the molecular basis of ageing. Much of our current understanding of ageing comes from genetic studies in model organisms seeking genes that either accelerate or decelerate the ageing process. These studies revealed not only causes of ageing, but also signaling mechanisms that both promote and protect against ageing. In all cases, the signaling pathways that influence lifespan are familiar mechanisms that regulate cellular metabolism, growth, proliferation, differentiation and survival. This review highlights the significant overlap in signaling mechanisms implicated in both the cellular response to genotoxic stress and regulation of organism lifespan.

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Control of apoptosis by Rel/NF-κB transcription factors

Cited by 1,143 publications

References 202 publications

Inhibition of RelA phosphorylation sensitizes apoptosis in constitutive NF-kappaB-expressing and chemoresistant cells

Inhibition of RelA phosphorylation sensitizes apoptosis in constitutive NF-kappaB-expressing and chemoresistant cells

High expression of RelA/p65 is associated with activation of nuclear factor-κB-dependent signaling in pancreatic cancer and marks a patient population with poor prognosis

Signaling mechanisms involved in the response to genotoxic stress and regulating lifespan

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