Novel Role for JNK as a Stress-activated Bcl2 Kinase

Deng, Xingming; Xiao, Lei; Liu, Wenhua; Gao, Fengqin; Ruvolo, Peter P.; May, W. Stratford

doi:10.1074/jbc.m100279200

Cited by 273 publications

(214 citation statements)

References 49 publications

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“…Chen et al recently reported that Bcl-xl is a target gene regulated by HiF-1α (3). in addition, JnK has been shown to induce cell apoptosis by phosphorylation (and inactivation) of the anti-apoptotic proteins of the Bcl-2 family (22)(23)(24). our results therefore demonstrated that HiF-1α, which is induced under hypoxic conditions, increased the expression of Bcl-xl; thus, the hypoxic condition led to the blockage of apoptosis by inhibiting the cleavage of caspase-3.…”

Section: Discussionsupporting

confidence: 55%

“…BPs also cause apoptosis and activate the MaPK and c-Jun n-terminal kinase (JnK) signaling pathways in osteoclasts and J774 macrophages in vitro (19). Various studies have shown that JnK induces cell apoptosis by phosphorylation and activation of the transcription factor p53 (20,21) or by phosphorylation (and inactivation) of the anti-apoptotic proteins of the Bcl-2 family (22)(23)(24).…”

Section: Introductionmentioning

confidence: 99%

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Protective effect of hypoxia on bisphosphonate‑related bone cell damage

et al. 2010

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Abstract. Bisphosphonates (BPs) are widely used for the prevention and treatment of osteoporosis. However, there have been numerous reports of side effects of BPs, including osteonecrosis of the jaw. in the present study, we investigated whether hypoxia inhibits BP-induced apoptosis, and examined the mechanisms of this inhibition. The cell viability of the MG 63 human osteoblast-like cell line treated with the nitrogencontaining (n)-BPs alendronate, risedronate and zoledronate was investigated, and hypoxia was assessed by crystal violet staining and the MTT assay, and by observing cell morphology. The effect of n-BPs and hypoxia on apoptotic cell signaling was evaluated using Western blotting, immunocytochemistry and the Tunel assay. The results of crystal violet staining and the MTT and Tunel assays showed that the n-BPs inhibited proliferation and induced apoptosis in MG 63 cells. Hypoxia significantly prevented N-BP-induced MG 63 cell apoptosis, and also attenuated BP-induced c-Jun n-terminal kinase (JnK) phosphorylation and Bcl-xl reduction. Hypoxia prevented BP-induced cell damage by blocking JnK phosphorylation and by regulating the Bcl-xl protein. Thus, hypoxia or hypoxia-related genes, including hypoxia-inducible factor 1α, may be a potential therapy for BP-related side effects such as osteonecrosis of the jaw.

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Section: Discussionsupporting

confidence: 55%

Section: Introductionmentioning

confidence: 99%

Protective effect of hypoxia on bisphosphonate‑related bone cell damage

et al. 2010

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“…Bcl-2 survival proteins are known to be inhibited by JNK. [58][59][60][61] In the case of Bcl-2 and Mcl-1, JNK inactivates these survival factors by direct phosphorylation. 24,62 However, ZBP-89 expression had no effect on Bcl-2.…”

Section: Ibmentioning

confidence: 99%

ZBP-89-induced apoptosis is p53-independent and requires JNK

et al. 2004

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ZBP-89 induces apoptosis in human gastrointestinal cancer cells through a p53-independent mechanism. To understand the apoptotic pathway regulated by ZBP-89, we identified downstream signal transduction targets. Ectopic expression of ZBP-89 induced apoptosis through the mitochondrial pathway and was accompanied by activation of all three MAP kinase subfamilies: JNK1/2, ERK1/2 and p38 MAP kinase. ZBP-89-induced apoptosis was markedly enhanced by ERK inhibition with U0126. In contrast, inhibiting JNK with a JNK1-specific peptide inhibitor or dominant-negative JNK2 expression abrogated ZBP-89-mediated apoptosis. The p38 inhibitor SB202190 had no effect on ZBP-89-induced cell death. Protein dephosphorylation assays revealed that ZBP-89 activates JNK via repression of JNK dephosphorylation. Oligonucleotide microarray analyses revealed that ectopic expression of ZBP-89 downregulated expression of the dual-specificity phosphatase MKP6. Overexpression of MKP6 blocked ZBP-89-induced JNK phosphorylation and PARP cleavage. In addition, ectopic expression of ZBP-89 repressed Bcl-xL and Mcl-1 expression, but had no effect on Bcl-2. Silencing ZBP-89 with small interfering RNA enhanced both Bcl-xL and Mcl-1 expression. Taken together, ZBP-89-mediated apoptosis occurs via a p53-independent mechanism that requires JNK activation.

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“…JNK phosphorylates members of the Bcl-2 family of proteins, such as Bcl-2 and Bcl-x L , and inactivates their antiapoptotic function. [20][21][22][23][24] Moreover, the ectopic expression of constitutively active JNK (using the MKK7-JNK1 fusion protein) efficiently induces apoptosis in wild-type cells, but not cells lacking the proapoptotic Bcl-2 family members, Bax and Bak, which are essential for the mitochondria-dependent apoptotic pathway. 25 Furthermore, JNK activates proapoptotic members of the Bcl-2 family, Bim and Bmf, resulting in activation of Bax and Bak.…”

Section: Introductionmentioning

confidence: 99%

Reactive oxygen species mediate crosstalk between NF-κB and JNK

et al. 2005

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The activation of NF-jB inhibits apoptosis via a mechanism involving upregulation of various antiapoptotic genes, such as cellular FLICE-inhibitory protein (c-FLIP), Bcl-x L , A1/Bfl-1, and X chromosome-liked inhibitor of apoptosis (XIAP). In contrast, the activation of c-Jun N-terminal kinase (JNK) promotes apoptosis in a manner that is dependent on the cell type and the context of the stimulus. Recent studies have indicated that one of the antiapoptotic functions of NF-jB is to downregulate JNK activation. Further studies have also revealed that NF-jB inhibits JNK activation by suppressing accumulation of reactive oxygen species (ROS). In this review, we will focus on the signaling crosstalk between the NF-jB and JNK cascades via ROS.

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Novel Role for JNK as a Stress-activated Bcl2 Kinase

Abstract: Interleukin (IL)-

Cited by 273 publications

References 49 publications

Protective effect of hypoxia on bisphosphonate‑related bone cell damage

Protective effect of hypoxia on bisphosphonate‑related bone cell damage

ZBP-89-induced apoptosis is p53-independent and requires JNK

Reactive oxygen species mediate crosstalk between NF-κB and JNK

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