RelA/NF-κB recruitment on the bax gene promoter antagonizes p73-dependent apoptosis in costimulated T cells

Cianfrocca, Roberta; Muscolini, Michela; Marzano, Valeria; Annibaldi, Alessandro; Marinari, Barbara; Levrero, Massimo; Costanzo, Antonio; Tuosto, Loretta

doi:10.1038/sj.cdd.4402264

Cited by 33 publications

(26 citation statements)

References 37 publications

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“…The recruitment of p300/CBP together with p73 on the bax promoter is necessary for p73-dependent Bax expression (32). By contrast, binding of the corepressor HDAC-1 is associated with the lost of p73 recruitment on the promoter and inhibition of bax gene trans-activation (22). We found that p73 transcriptional activity on the bax promoter is inhibited in cisplatin-resistant cells, and TSA treatment restores p73-dependent transcription of bax (Fig.…”

Section: Discussionmentioning

confidence: 66%

Trichostatin A up-regulates p73 and induces Bax-dependent apoptosis in cisplatin-resistant ovarian cancer cells

Muscolini

Cianfrocca

Sajeva

et al. 2008

Molecular Cancer Therapeutics

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Several studies in the last years evidenced that deregulation of proapoptotic and antiapoptotic pathways are key players in the onset and maintenance of chemoresistance in advanced ovarian cancers. To characterize the signaling events and molecules involved in the acquisition of cisplatin resistance, we used the human ovarian cancer cell line A2780 and its derivative cisplatin-resistant subline A2780 CIS. We found that the mitochondrial intrinsic apoptotic pathway, induced by cis-dichlorodiammineplatinum (CDDP) in A2780 wild-type cells, was compromised in the resistant subline CIS. The analysis of expression of proteins involved in mitochondriadependent apoptosis revealed a role of Bax and p73 but not p53. Indeed, we found that CDDP treatment induced the up-regulation of p53 in both sensitive and resistant A2780 cell lines. By contrast, p73 and Bax expressions were compromised in resistant cells. Pretreatment of resistant A2780 CIS cells with the histone deacetylase inhibitor trichostatin A overcomes apoptosis resistance to CDDP by restoring both p73 and Bax but not p53 expression. Altogether, these data indicate that p73, but not p53, is involved in the regulation of apoptosis susceptibility to cisplatin in A2780 ovarian cancer cells and evidence a key contribution of histone deacetylase activation in the acquisition of chemotherapy resistance in human ovarian cancer cells.

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Section: Discussionmentioning

confidence: 66%

Trichostatin A up-regulates p73 and induces Bax-dependent apoptosis in cisplatin-resistant ovarian cancer cells

Muscolini

Cianfrocca

Sajeva

et al. 2008

Molecular Cancer Therapeutics

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“…Indeed, irradiation of activated T cells results in p53-independent apoptosis. Interestingly, irradiation of activated T cells recruits p73 to the Bax promoter, and this effect is antagonized by p50/RelA (47). When might a failure to engage NF-κB during T-cell activation occur during normal immune responses?…”

Section: Discussionmentioning

confidence: 99%

NF-κB inhibits T-cell activation-induced, p73-dependent cell death by induction of MDM2

Busuttil

Droin

McCormick

et al. 2010

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

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NF-κB is a key transcription factor involved in the regulation of T-cell activation and proliferation upon engagement of the T-cell receptor (TCR). T cells that lack the IκB kinase (IKKβ) are unable to activate NF-κB, and rapidly undergo apoptosis upon activation. NF-κB activation following T-cell receptor engagement induces the expression of Mdm2 through interaction with NF-κB sites in its P1 promoter, and enforced expression of Mdm2 protected T cells deficient for NF-κB activation from activation-induced cell death. In T cells with intact NF-κB signaling, ablation or pharmacologic inhibition of Mdm2 resulted in activation-induced apoptosis. Mdm2 coprecipitates with p73 in activated T cells, and apoptosis induced by inhibition of Mdm2 was p73-dependent. Further, Bim was identified as a p73 target gene required for cell death induced by Mdm2 inhibition, and a p73-responsive element in intron 1 of Bim was characterized. Our results demonstrate a pathway for survival of activated T cells through NF-κB–induced Mdm2, which blocks Bim-dependent apoptosis through binding and inhibition of p73.

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“…In addition, the inhibition of NFκB activity also reduces possible direct or indirect repression of Bax expression by NFκB. 38,44 The strategy specifically directed to the transient activation of Wip1 in patients loop downregulating NFκB function following exposure to an inflammatory stress. 42,43 To test whether negative regulation of NFκB function by overexpressed Wip1 contributed to the increased sensitivity to cisplatin, we determined the levels of p65 S536 phosphorylation in our system.…”

Section: Discussionmentioning

confidence: 99%

Wip1 sensitizes p53-negative tumors to apoptosis by regulating the Bax/Bcl-x_Lratio

et al. 2012

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Wip1 is a stress-response phosphatase that negatively regulates several tumor suppressors, including p53. In a sizeable fraction of tumors, overexpression or amplification of Wip1 compromises p53 functions; inhibition of Wip1 activity is an attractive strategy for improving treatment of these tumors. However, over half of human tumors contain mutations in the p53 gene or have lost both alleles. Recently, we observed that in cancer cells lacking wild-type p53, reduction of Wip1 expression was ineffective, whereas, surprisingly, overexpression of Wip1 increased anticancer drug sensitivity. The increased sensitivity resulted from activation of the intrinsic pathway of apoptosis through increased levels of the pro-apoptotic protein Bax and decreased levels of the anti-apoptotic protein Bcl-x L . We showed that interaction of Wip1 and the transcription factor RUNX2, specifically through dephosphorylation of RUNX2 phospho-S432, resulted in increased expression of Bax. Interestingly, overexpression of Wip1 increased drug sensitivity only in the p53-negative tumor cells while protecting the wild-type, p53-containing normal cells from drug-induced collateral injury. Here, we provide evidence that Wip1 overexpression decreases expression of Bcl-x L through negative regulation of NFκB activity. Thus, Wip1 overexpression increases the sensitivity of p53-negative cancer cells to anticancer drugs by separately affecting Bax and Bcl-x L protein levels.

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RelA/NF-κB recruitment on the bax gene promoter antagonizes p73-dependent apoptosis in costimulated T cells

Cited by 33 publications

References 37 publications

Trichostatin A up-regulates p73 and induces Bax-dependent apoptosis in cisplatin-resistant ovarian cancer cells

Trichostatin A up-regulates p73 and induces Bax-dependent apoptosis in cisplatin-resistant ovarian cancer cells

NF-κB inhibits T-cell activation-induced, p73-dependent cell death by induction of MDM2

Wip1 sensitizes p53-negative tumors to apoptosis by regulating the Bax/Bcl-x_Lratio

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RelA/NF-κB recruitment on the bax gene promoter antagonizes p73-dependent apoptosis in costimulated T cells

Cited by 33 publications

References 37 publications

Trichostatin A up-regulates p73 and induces Bax-dependent apoptosis in cisplatin-resistant ovarian cancer cells

Trichostatin A up-regulates p73 and induces Bax-dependent apoptosis in cisplatin-resistant ovarian cancer cells

NF-κB inhibits T-cell activation-induced, p73-dependent cell death by induction of MDM2

Wip1 sensitizes p53-negative tumors to apoptosis by regulating the Bax/Bcl-xLratio

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Wip1 sensitizes p53-negative tumors to apoptosis by regulating the Bax/Bcl-x_Lratio