A20 RNA expression is associated with undifferentiated nasopharyngeal carcinoma and poorly differentiated head and neck squamous cell carcinoma

Codd, Jane D.; Salisbury, Jonathan R.; Packham, Graham; Nicholson, Linda J.

doi:10.1002/(sici)1096-9896(199904)187:5<549::aid-path278>3.0.co;2-o

Cited by 48 publications

(19 citation statements)

References 25 publications

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“…22 The preferential expression of A20 in poorly differentiated carcinomas suggest that its anti-apoptotic function may play a role in the tumor pathogenesis. 27 Furthermore, due to its dual role as an anti-apoptotic and anti-inflammatory protein it may have therapeutic potential e.g. in tissue transplantation and diabetes mellitus.…”

Section: Discussionmentioning

confidence: 97%

“…26 Furthermore, A20 expression in human tumors has been suggested to be linked to enhanced tumorigenesis via resistance to apoptosis. 20,27 A20 binds to TRAF2 involved in TNF-induced activation of NF-kB and AP-1 and to TRAF6 implicated in the IL-1-induced activation of these transcription factors. 4,24,28,29 Yeast two-hybrid studies have also revealed binding of A20 zinc finger domain to 14-3-3 chaperone proteins, whose expression alters the distribution of A20 in the cytosol from punctuate to diffuse pattern.…”

Section: Introductionmentioning

confidence: 99%

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A20 zinc finger protein inhibits TNF-induced apoptosis and stress response early in the signaling cascades and independently of binding to TRAF2 or 14-3-3 proteins

2001

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A20 zinc finger protein is a negative regulator of tumor necrosis factor (TNF)-induced signaling pathways leading to apoptosis, stress response and inflammation. A20 has been shown to bind to TNF-receptor-associated factor 2 (TRAF2) and 14-3-3 chaperone proteins. Our data indicate that the zinc finger domain of A20 is sufficient and that neither TRAF2 nor 14-3-3 binding is necessary for the inhibitory effects of A20. Mutations in the 14-3-3 binding site of A20 did, however, result in a partial cleavage of A20 protein suggesting that 14-3-3 chaperone proteins may stabilize A20. Furthermore, we show that A20 acts early in TNF-induced signaling cascades blocking both TNF-induced rapid activation of c-Jun Nterminal kinase and processing of the receptor-associated caspase-8. Taken together our data indicate that the zinc finger domain of A20 contains all necessary functional domains required for the inhibition of TNF signaling and that A20 may function at the level of the receptor signaling complex. Cell Death and Differentiation (2001) 8, 265 ± 272.

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Section: Discussionmentioning

confidence: 97%

Section: Introductionmentioning

confidence: 99%

A20 zinc finger protein inhibits TNF-induced apoptosis and stress response early in the signaling cascades and independently of binding to TRAF2 or 14-3-3 proteins

2001

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“…13 Resistance to apoptosis has also been associated with the expression of A20, a putative antiapoptotic protein of EBV that can be, but is not only, induced by LMP -1. 9 One approach to address the influence of EBV status on cisplatin or p53 gene therapy would be to use a pair of isogenic cell lines with differing EBV status. Only one group had successfully infected an epithelial cell line with EBV, but our laboratory was unable to duplicate these results.…”

Section: Discussionmentioning

confidence: 99%

Cisplatin chemotherapy plus adenoviral p53 gene therapy in EBV-positive and -negative nasopharyngeal carcinoma

Weinrib

Donovan

et al. 2001

Cancer Gene Ther

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We have previously shown that the introduction of human recombinant wild -type p53 mediated by an adenoviral vector ( Ad5CMV -p53 ), either alone or delivered in combination with ionizing radiation, was cytotoxic to two nasopharyngeal carcinoma ( NPC ) cell lines. To further explore the potential therapeutic role for gene therapy, the combination of Ad5CMV -p53 and cisplatin was examined in two NPC cell lines, CNE -1 and C666 -1. The C666 -1 cells are particularly relevant because they express Epstein -Barr virus latent gene products analogous to human NPC in situ. Cells were infected with 5 pfu / cell of Ad5CMV -p53 or Ad5CMV --gal, followed by exposure to increasing doses of cisplatin. Clonogenic and MTT assays were used to assess the sensitivity of cells to these treatments, and apoptosis was also quantified. The combination of Ad5CMV -p53 and cisplatin resulted in approximately 25% greater cytotoxicity compared to that observed with cisplatin alone in either cell line. Apoptosis was induced in approximately 50% of cells following administration of both Ad5CMV -p53 and cisplatin, but was induced in considerably fewer cells following either treatment alone. The two modalities appeared to interact in an additive manner. Ad5CMV -p53 gene therapy resulted in the expression of biologically active p53 protein, shown by induction of p21 WAF1 / CIP1 . Cisplatin treatment showed little effect on either p53 or p21 WAF1 / CIP1 expression. Therefore, both p53 gene therapy and cisplatin chemotherapy demonstrated cytotoxicity mediated by apoptosis despite the presence of EBV gene products in the C666 -1 cells, but it appears that the two modalities induce cytotoxicity by independent pathways. Cancer Gene Therapy ( 2001 ) 8, 352 ± 360

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“…A20 mRNA is upregulated in undifferentiated nasopharyngeal carcinoma and poorly differentiated head and neck squamous cell carcinomas (SCCs) of the skin, suggesting that A20 has a part in the pathogenesis of these epithelial malignancies. In contrast, no A20 mRNA is detected in normal samples of squamous epithelial tissues or in well-differentiated SCCs [6]. A20 expression in estrogen receptor (ER) and progesterone receptor (PR) negative breast tumour cells in vivo has been associated with poor prognosis.…”

Section: Expression Of A20mentioning

confidence: 99%

Expression, biological activities and mechanisms of action of A20 (TNFAIP3)

Verstrepen

Verhelst

Loo

et al. 2010

Biochemical Pharmacology

185

160

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A20 (also known as TNFAIP3) is a cytoplasmic protein that plays a key role in the negative regulation of inflammation and immunity. Polymorphisms in the A20 gene locus have been identified as risk alleles for multiple human autoimmune diseases, and A20 has also been proposed to function as a tumor suppressor in several human B-cell lymphomas. A20 expression is strongly induced by multiple stimuli, including the proinflammatory cytokines TNF and IL-1, and microbial products that trigger pathogen recognition receptors, such as Toll-like receptors. A20 functions in a negative feedback loop, which mediates its inhibitory functions by downregulating key proinflammatory signaling pathways, including those controlling NF-κB-and IRF3-dependent gene expression. Activation of these transcription factors is controlled by both K48-and K63-polyubiquitination of upstream signaling proteins, respectively triggering proteasome-mediated degradation or interaction with other signaling proteins. A20 turns off NF-B and IRF3 activation by modulating both types of ubiquitination. Induction of K48-polyubiquitination by A20 involves its C-terminal zincfinger ubiquitin-binding domain, which may promote interaction with E3 ligases, such as Itch and RNF11 that are involved in mediating A20 inhibitory functions. A20 is thought to promote de-ubiquitination of K63-polyubiquitin chains either directly, due to its N-terminal deubiquitinase domain, or by disrupting the interaction between E3 and E2 enzymes that catalyze K63-polyubiquitination. A20 is subject to different mechanisms of regulation, including phosphorylation, proteolytic processing, and association with ubiquitin binding proteins. Here we review the expression and biological activities of A20, as well as the underlying molecular mechanisms.

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A20 RNA expression is associated with undifferentiated nasopharyngeal carcinoma and poorly differentiated head and neck squamous cell carcinoma

Cited by 48 publications

References 25 publications

A20 zinc finger protein inhibits TNF-induced apoptosis and stress response early in the signaling cascades and independently of binding to TRAF2 or 14-3-3 proteins

A20 zinc finger protein inhibits TNF-induced apoptosis and stress response early in the signaling cascades and independently of binding to TRAF2 or 14-3-3 proteins

Cisplatin chemotherapy plus adenoviral p53 gene therapy in EBV-positive and -negative nasopharyngeal carcinoma

Expression, biological activities and mechanisms of action of A20 (TNFAIP3)

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