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

Lademann, Ulrik; Kallunki, Tuula; Jäättelä, Marja

doi:10.1038/sj.cdd.4400805

Cited by 47 publications

(33 citation statements)

References 41 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…A20 inhibits TNF-induced proapoptotic signaling by inhibiting both the activation of caspase 8 and the activation of c-Jun (54). However, neither the drug-induced proapoptotic mechanisms nor the A20-induced antiapoptotic mechanisms have been investigated in this study; our observation of cytotoxicity despite high antiapoptotic A20 mRNA levels may suggest an overriding mechanism.…”

Section: Discussioncontrasting

confidence: 47%

Connectivity mapping (ssCMap) to predict A20-inducing drugs and their antiinflammatory action in cystic fibrosis

Malcomson

Wilson

Veglia

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

Cystic fibrosis (CF) lung disease is characterized by chronic and exaggerated inflammation in the airways. Despite recent developments to therapeutically overcome the underlying functional defect in the cystic fibrosis transmembrane conductance regulator, there is still an unmet need to also normalize the inflammatory response. The prolonged and heightened inflammatory response in CF is, in part, mediated by a lack of intrinsic down-regulation of the proinflammatory NF-κB pathway. We have previously identified reduced expression of the NF-κB down-regulator A20 in CF as a key target to normalize the inflammatory response. Here, we have used publicly available gene array expression data together with a statistically significant connections' map (sscMap) to successfully predict drugs already licensed for the use in humans to induce A20 mRNA and protein expression and thereby reduce inflammation. The effect of the predicted drugs on A20 and NF-κB(p65) expression (mRNA) as well as proinflammatory cytokine release (IL-8) in the presence and absence of bacterial LPS was shown in bronchial epithelial cells lines (16HBE14o−, CFBE41o−) and in primary nasal epithelial cells from patients with CF (Phe508del homozygous) and non-CF controls. Additionally, the specificity of the drug action on A20 was confirmed using cell lines with tnfαip3 (A20) knockdown (siRNA). We also show that the A20-inducing effect of ikarugamycin and quercetin is lower in CF-derived airway epithelial cells than in non-CF cells.A20 | NF-κB | connectivity mapping | drug repositioning | CF airway inflammation

show abstract

Section: Discussioncontrasting

confidence: 47%

Connectivity mapping (ssCMap) to predict A20-inducing drugs and their antiinflammatory action in cystic fibrosis

Malcomson

Wilson

Veglia

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

show abstract

“…Other studies found that GADD45b/MyD118, an NF-kB target gene that belongs to the GADD45 family of factors involved in cell cycle control and DNA repair, is involved in suppressing JNK signaling at the level of JNKK2/MKK7 (De Smaele et al, 2001;Papa et al, 2003). The NF-kB-regulated zinc-finger protein A20, which antagonizes TNF induction of JNK, is another possible contender (Lademann et al, 2001). Nevertheless, elimination of XIAP in MEFs was not sufficient to abolish inactivation of JNK by NF-kB (A Lin, personal communication).…”

Section: Crosstalk Between Nf-kb and Jnk: Something To Live Formentioning

confidence: 99%

To be, or not to be: NF-κB is the answer – role of Rel/NF-κB in the regulation of apoptosis

et al. 2003

View full text Add to dashboard Cite

“…More importantly, the ectopic expression of both A20 and c-IAP1 conferred significant protection against apoptosis induced by luteolin and TNFa (Figure 7). Zinc-finger protein A20 is a NF-kB inducible gene (Krikos et al, 1992) and one of its important functions is inhibition of TNFamediated apoptosis (Song et al, 1996;Lademann, et al, 2001). A20-deficient cells have been reported to be highly susceptible to apoptosis induced by TNFa (Lee et al, 2000).…”

Section: Discussionmentioning

confidence: 99%

Luteolin sensitizes tumor necrosis factor-α-induced apoptosis in human tumor cells

2004

View full text Add to dashboard Cite

Tumor necrosis factor-a (TNFa) activates both cell death and cell survival pathways, which render most cancer cells resistant to its cytotoxicity. In this study, we found that pretreatment with luteolin, a plant flavonoid, greatly sensitized TNFa-induced apoptotic cell death in a number of human cancer cell lines; including colorectal cancer COLO205, HCT116 cells and cervical cancer HeLa cells. In the search of the molecular mechanisms responsible for the sensitization effect of luteolin, we discovered that luteolin inhibited TNFa-induced activation of nuclear transcription factor-kappa B (NF-jB), the main survival factor in TNFa signaling. As a result, luteolin suppressed the expression of NF-jB-targeted antiapoptotic genes, including A20 and cellular inhibitor of apoptosis protein-1 (c-IAP1). The role of A20 and c-IAP1 was further confirmed by ectopic expression of these two genes, which significantly protected cell death induced by luteolin followed by TNFa. In addition, inhibition of NF-jB by luteolin led to augmentation and prolongation of c-Jun N-terminal kinase (JNK) activation induced by TNFa. Suppression of JNK activation, either by a synthetic JNK inhibitor (SP600125) or by overexpression of the dominant negative forms of JNK kinase 1 (JNKK1) and JNK kinase 2 (JNKK2), conferred significant protection against apoptotic cell death induced by luteolin and TNFa, suggesting that NF-jB and JNK are closely associated with the sensitization effect of luteolin. Data from this study reveal a novel function of luteolin and enhance the value of luteolin as an anticancer agent.

show abstract

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

Cited by 47 publications

References 41 publications

Connectivity mapping (ssCMap) to predict A20-inducing drugs and their antiinflammatory action in cystic fibrosis

Connectivity mapping (ssCMap) to predict A20-inducing drugs and their antiinflammatory action in cystic fibrosis

To be, or not to be: NF-κB is the answer – role of Rel/NF-κB in the regulation of apoptosis

Luteolin sensitizes tumor necrosis factor-α-induced apoptosis in human tumor cells

Contact Info

Product

Resources

About