Differential contribution of Puma and Noxa in dual regulation of p53-mediated apoptotic pathways

Shibue, Tsukasa; Suzuki, Saori; Okamoto, Hiroki; Yoshida, Hiroki; Ohba, Yusuke; Takaoka, Akinori; Taniguchi, Tadatsugu

doi:10.1038/sj.emboj.7601359

Cited by 91 publications

(83 citation statements)

References 54 publications

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“…The induction of PUMA and NOXA was speculated to be another crucial event mediating the synergistic apoptosis. PUMA and NOXA have been shown to be the transcriptional targets of p53 and essential mediators in p53-induced apoptosis (39)(40)(41)(42). In the current study, we found that both TH-302 and bortezomib can activate p53 and its downstream target gene p21 WAF1/CIP1 in multiple myeloma cells expressing wild-type p53 (Fig.…”

Section: Discussionsupporting

confidence: 53%

Synergistic Induction of Apoptosis in Multiple Myeloma Cells by Bortezomib and Hypoxia-Activated Prodrug TH-302, In Vivo and In Vitro

Valckenborgh

et al. 2013

Molecular Cancer Therapeutics

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Recently, we showed that hypoxia is a critical microenvironmental factor in multiple myeloma, and that the hypoxia-activated prodrug TH-302 selectively targets hypoxic multiple myeloma cells and improves multiple disease parameters in vivo. To explore approaches for sensitizing multiple myeloma cells to TH-302, we evaluated in this study the antitumor effect of TH-302 in combination with the clinically used proteasome inhibitor bortezomib. First, we show that TH-302 and bortezomib synergistically induce apoptosis in multiple myeloma cell lines in vitro. Second, we confirm that this synergism is related to the activation of caspase cascades and is mediated by changes of Bcl-2 family proteins. The combination treatment induces enhanced cleavage of caspase-3/8/9 and PARP, and therefore triggers apoptosis and enhances the cleavage of proapoptotic BH3-only protein BAD and BID as well as the antiapoptotic protein Mcl-1. In particular, TH-302 can abrogate the accumulation of antiapoptotic Mcl-1 induced by bortezomib, and decreases the expression of the prosurvival proteins Bcl-2 and Bcl-xL. Furthermore, we found that the induction of the proapoptotic BH3-only proteins PUMA (p53-upregulated modulator of apoptosis) and NOXA is associated with this synergism. In response to the genotoxic and endoplasmic reticulum stresses by TH-302 and bortezomib, the expression of PUMA and NOXA were upregulated in p53-dependent and -independent manners. Finally, in the murine 5T33MMvv model, we showed that the combination of TH-302 and bortezomib can improve multiple disease parameters and significantly prolong the survival of diseased mice. In conclusion, our studies provide a rationale for clinical evaluation of the combination of TH-302 and bortezomib in patients with multiple myeloma.

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Section: Discussionsupporting

confidence: 53%

Synergistic Induction of Apoptosis in Multiple Myeloma Cells by Bortezomib and Hypoxia-Activated Prodrug TH-302, In Vivo and In Vitro

Valckenborgh

et al. 2013

Molecular Cancer Therapeutics

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“…The BH3-only protein Bax, PUMA, and NOXA play important roles in mitochondrial apoptotic pathways induced in p53-dependent and -independent manners (3,(39)(40)(41). Perp, Pig11, and Wig1 are also involved in apoptosis (42)(43)(44).…”

Section: Discussionmentioning

confidence: 99%

SHP-2 tyrosine phosphatase inhibits p73-dependent apoptosis and expression of a subset of p53 target genes induced by EGCG

Amin¹,

Thakur²,

Paul³

et al. 2007

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

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Green tea polyphenol, epigallocatechin-3-gallate (EGCG) differentially regulates the cellular growth of cancer cells in a p53-dependent manner through apoptosis and/or cell cycle arrest. In an effort to further elucidate the mechanism of differential growth regulation by EGCG, we have investigated the role of the tyrosine phosphatase, SHP-2. Comparing the responses of mouse embryonic fibroblasts (MEFs), expressing either WT or functionally inactive/truncated SHP-2, we find that inactivation of SHP-2 remarkably sensitizes cells to EGCG-mediated killing. MEFs lacking functional SHP-2 undergo massive apoptosis upon treatment with EGCG. By comparing gene expression profiles, we have identified a set of transcriptional targets of p53 that are differentially modulated in cells undergoing apoptosis. Western blot and real-time PCR analyses of a select group of genes further confirm that the expression is SHP-2-dependent. Similar observations were made in MEFs lacking p53, confirming that the expression of these ''p53 target genes'' is p53-independent. In addition, EGCG treatment induced the expression of p73 mRNA and protein in both cell types, but not p63. Inactivation of p73 in cells expressing nonfunctional SHP-2 markedly inhibited apoptosis and p53 target gene expression. Although phosphorylation of JNK is differentially regulated by SHP2, it was found to be dispensable for EGCG-induced apoptosis and p53 target gene expression. Our results have identified SHP-2 as a negative regulator of EGCG-inducedapoptosis and have identified a subset of p53 target genes whose expression is paradoxically not mediated by p53 but by one of its family members, p73.green tea ͉ MAPK pathway ͉ mouse embryonic fibroblasts ͉ transcriptional activation

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“…Finally, PUMA and NOXA are also upregulated during ER stress, both have been found at the ER, and both play a role in ER Ca 2 þ release (Reimertz et al, 2003;Luo et al, 2005;Rao et al, 2006;Shibue et al, 2006;Kieran et al, 2007;Nickson et al, 2007;Hassan et al, 2008). PUMAmediated apoptosis has been linked to activation of caspase-12 and is reduced by caspase-12 knockdown or deficiency (Shibue et al, 2006).…”

Section: Pathways Leading To Er Stress-induced Apoptosismentioning

confidence: 99%

“…PUMA was shown to induce both caspasedependent and caspase-independent MOMP, with the caspase-dependent pathway proceeding through calpain-associated activation of caspase-12 (Shibue et al, 2006), whereas NOXA led to both cytochrome c release and activation of JNK/p38 mitogen-activated protein kinase (Hassan et al, 2008).…”

Section: Apoptosis and Er Ca 2 þ Release: Bh3 Only Proteinsmentioning

confidence: 99%

The endoplasmic reticulum in apoptosis and autophagy: role of the BCL-2 protein family

2008

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Differential contribution of Puma and Noxa in dual regulation of p53-mediated apoptotic pathways

Cited by 91 publications

References 54 publications

Synergistic Induction of Apoptosis in Multiple Myeloma Cells by Bortezomib and Hypoxia-Activated Prodrug TH-302, In Vivo and In Vitro

Synergistic Induction of Apoptosis in Multiple Myeloma Cells by Bortezomib and Hypoxia-Activated Prodrug TH-302, In Vivo and In Vitro

SHP-2 tyrosine phosphatase inhibits p73-dependent apoptosis and expression of a subset of p53 target genes induced by EGCG

The endoplasmic reticulum in apoptosis and autophagy: role of the BCL-2 protein family

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