Activation of Bak and Bax through c-Abl-Protein Kinase Cδ-p38 MAPK Signaling in Response to Ionizing Radiation in Human Non-small Cell Lung Cancer Cells

Choi, Soon-Young; Kim, Minjung; Kang, Chang‐Mo; Bae, Sangwoo; Cho, Chul-Koo; Soh, Jae-Won; Kim, Jae Hong; Kang, Seongman; Chung, Hee Yong; Lee, Yun‐Sil; Lee, Su‐Jae

doi:10.1074/jbc.m512000200

Cited by 86 publications

(56 citation statements)

References 57 publications

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“…Moreover, inhibition of p38MAPK almost completely prevents radiation-induced Bax translocation to the mitochondria, release of cytochrome c into the cytosol, caspase-3 activation, and PARP cleavage (50). These results are in good agreement with the fact that p38MAPK mediates dysfunction of mitochondria and subsequent induces caspase activation in several cell types (38,50).…”

Section: Discussionsupporting

confidence: 78%

“…Recently it has been demonstrated that p38MAPK induces apoptosis by regulating the conformation of Bax in response to various stimuli, including UVB, cisplatin, taxol, and nocodazole (28,38,46,47). In this study, we found that inhibition of p38MAPK inhibited the accumulation of Bax protein (Fig.…”

Section: Discussionsupporting

confidence: 59%

“…It has been shown that p38MAPK acts at early step(s) prior to dysfunction of mitochondria during apoptotic cell death in several model systems (38). We next investigated whether the upregulation of Bax, downregulation of Bcl-2, and cytochrome c release in response to genipin treatment were dependent on p38MAPK activation.…”

Section: Role Of P38mapk In Mediating Bax Expression and Cytochrome Cmentioning

confidence: 99%

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P38 MAP Kinase Mediates Apoptosis After Genipin Treatment in Non^|^ndash;Small-Cell Lung Cancer H1299 Cells via a Mitochondrial Apoptotic Cascade

et al. 2013

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Abstract. Genipin, an active constituent of Gardenia fruit, has been reported to show an antitumor effect in several cancer cell systems. Here, we demonstrate how genipin exhibits a strong apoptotic cell death effect in human non-small-cell lung cancer H1299 cells. Genipin-mediated decrease in cell viability was observed through apoptosis as demonstrated by induction of a sub-G 1 peak through flow cytometry, DNA fragmentation measured by TUNEL assay, and cleavage of poly ADP-ribose-polymerase. During genipin-induced apoptosis, the mitochondrial execution pathway was activated by caspase-9 and -3 activation as examined by a kinetic study, cytochrome c release, and a dose-dependent increase in Bax/Bcl-2 ratio. A search for the downstream pathway reveals that genipin-induced apoptosis was mediated by an increase in phosphorylated p38MAPK expression, which further activated downstream signaling by phosphorylating ATF-2. SB203580, a p38MAPK inhibitor, markedly blocked the formation of TUNEL-positive apoptotic cells in genipin-treated cells. Besides, the interference of p38MAPK inhibited Bax expression and cytochrome c release. Altogether, our observations imply that genipin causes increased levels of Bax in response to p38MAPK signaling, which results in the initiation of mitochondrial death cascade, and therefore it holds promise as a potential chemotherapeutic agent for the treatment of H1299 cells.

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Section: Discussionsupporting

confidence: 78%

Section: Discussionsupporting

confidence: 59%

Section: Role Of P38mapk In Mediating Bax Expression and Cytochrome Cmentioning

confidence: 99%

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P38 MAP Kinase Mediates Apoptosis After Genipin Treatment in Non^|^ndash;Small-Cell Lung Cancer H1299 Cells via a Mitochondrial Apoptotic Cascade

et al. 2013

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“…Thus, this study shows that Gα s-cAMP signaling system protects SH-SY5Y neuroblastoma cells by slowing down Bcl-xL mRNA and protein following gamma ray-irradiation. Moreover, Gα s was found to represse ionizing radiation-induced up-regulation of Bak in SH-SY5Y human neuroblastoma cells, which also favors cell survival (Choi et al, 2006), indicating Gαs-cAMP signaling system protects cells against radiation-induced apoptosis by affecting multiple pro-apoptotic and anti-apoptotic Bcl-2 family proteins.…”

Section: Discussionmentioning

confidence: 96%

Inhibition of γ ray-induced apoptosis by stimulatory heterotrimeric GTP binding protein involves Bcl-xL down-regulation in SH-SY5Y human neuroblastoma cells

Kim

Seo

et al. 2007

Exp Mol Med

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Heterotrimeric GTP-binding proteins (G proteins) transduce extracellular signals into intracellular signals by activating effector molecules including adenylate cyclases that catalyze cAMP formation, and thus regulate various cellular responses such as metabolism, proliferation, and apoptosis. cAMP signaling pathways have been reported to protect cells from ionizing radiation-induced apoptosis, but however, the protective mechanism is not clear. Therefore, this study aimed to investigate the signaling molecules and the mechanism mediating the anti-apoptotic action of cAMP signaling system in radiation-induced apoptosis. Stable expression of a constitutively active mutant of Gα s (Gα sQL) protected gamma ray-induced apoptosis which was assessed by analysis of the cleavages of PARP, caspase-9, and caspase-3 and cytochrome C release in SH-SY5Y human neuroblastoma cells. GαsQL repressed the gamma ray-induced down-regulation of Bcl-xL protein, but transfection of Bcl-xL siRNA increased the gamma ray-induced apoptosis and abolished the anti-apoptotic effect of Gα sQL. Gα sQL decreased the degradation rate of Bcl-xL protein, and it also restrained the decrease in Bcl-xL mRNA by increasing the stability following ionizing irradiation. Furthermore, prostaglandin E2 that activates Gαs was found to protect gamma ray-induced apoptosis, and the protective effect was abolished by treatment with prostanoid receptor antagonist specific to EP2/4R subtype. Moreover, specific agonists for adenosine A1 receptor that inhibits cAMP signaling pathway augmented gamma ray-induced apoptosis. From this study, it is concluded that Gαs-cAMP signaling system can protect SH-SY5Y cells from gamma ray-induced apoptosis partly by restraining down-regulation of Bcl-xL expression, suggesting that radiation-induced apoptosis can be modulated by GPCR ligands to improve the efficiency of radiation therapy.

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“…The phosphorylation of p38 by the PKCδ Y311E mutant contributed to the apoptotic effect of this mutant since the p38 inhibitor, SB203580, abrogated the apoptotic effect induced by the PKCδ Y311E mutant. The mechanisms by which the PKCδ Y311E induces phosphorylation of p38 are currently not known, however PKCδ has been associated with the phosphorylation of p38 [29] and a recent study demonstrated that PKCδ was tyrosine phosphorylated by c-Abl in response to ionizing radiation which led to the activation of p38 [30]. The activation of p38 by the PKCδ Y311E mutant may be also associated with the decreased expression of XIAP as a recent report suggested that p38 inhibited Erk activity which is important for maintaining XIAP levels [31].…”

Section: Discussionmentioning

confidence: 99%

Tyrosine 311 is phosphorylated by c-Abl and promotes the apoptotic effect of PKCδ in glioma cells

Lü

Finnis

Xiang

et al. 2007

Biochemical and Biophysical Research Communications

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In this study, we characterized the phosphorylation of tyrosine 311 and its role in the apoptotic function of PKCδ in glioma cells. We found that c-Abl phosphorylated PKCδ on tyrosine 311 in response to H 2 O 2 and that this phosphorylation contributed to the apoptotic effect of H 2 O 2 . In contrast, Src, Lyn and Yes were not involved in the phosphorylation of tyrosine 311 by H 2 O 2 . A phosphomimetic PKCδ mutant, in which tyrosine 311 was mutated to glutamic acid (PKCδ Y311E), induced a large degree of cell apoptosis. Overexpression of the PKCδ Y311E mutant induced the phosphorylation of p38 and inhibition of p38 abolished the apoptotic effect of the PKCδ mutant. These results suggest an important role of tyrosine 311 in the apoptotic function of PKCδ and implicate c-Abl as the kinase that phosphorylates this tyrosine.

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Activation of Bak and Bax through c-Abl-Protein Kinase Cδ-p38 MAPK Signaling in Response to Ionizing Radiation in Human Non-small Cell Lung Cancer Cells

Cited by 86 publications

References 57 publications

P38 MAP Kinase Mediates Apoptosis After Genipin Treatment in Non^|^ndash;Small-Cell Lung Cancer H1299 Cells via a Mitochondrial Apoptotic Cascade

P38 MAP Kinase Mediates Apoptosis After Genipin Treatment in Non^|^ndash;Small-Cell Lung Cancer H1299 Cells via a Mitochondrial Apoptotic Cascade

Inhibition of γ ray-induced apoptosis by stimulatory heterotrimeric GTP binding protein involves Bcl-xL down-regulation in SH-SY5Y human neuroblastoma cells

Tyrosine 311 is phosphorylated by c-Abl and promotes the apoptotic effect of PKCδ in glioma cells

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