Targeting of the c-Abl Tyrosine Kinase to Mitochondria in the Necrotic Cell Death Response to Oxidative Stress

Kumar, Shailendra; Bharti, Ajit; Mishra, Neerad C.; Raina, Deepak; Kharbanda, Surender; Saxena, Satya; Küfe, Donald

doi:10.1074/jbc.m101414200

Cited by 101 publications

(83 citation statements)

References 28 publications

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“…Recently, STI571 also abrogated cell death responses following oxidative stress, presumably by inhibiting c-Abl tyrosine kinase activity (45). Our data strongly suggest that Gleevec TM may be ill suited in conjunction with temozolomide or cisplatin or other clinically used alkylating agents for efficacious cancer therapy.…”

Section: Discussionmentioning

confidence: 77%

DNA Mismatch Repair-dependent Activation of c-Abl/p73α/GADD45α-mediated Apoptosis

Morales

Hwang

et al. 2008

Journal of Biological Chemistry

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2 arrest and apoptosis. Loss of p53 function by E6 expression, dominant-negative p53, or stable p53 knockdown failed to prevent MMR-dependent G 2 arrest, apoptosis, or lethality. MMR-dependent c-Abl-mediated p73␣ and GADD45␣ protein up-regulation after MNNG exposure prompted us to examine c-Abl/p73␣/GADD45␣ signaling in cell death responses. STI571 (Gleevec TM , a c-Abl tyrosine kinase inhibitor) and stable c-Abl, p73␣, and GADD45␣ knockdown prevented MMR-dependent apoptosis. Interestingly, stable p73␣ knockdown blocked MMR-dependent apoptosis, but not G 2 arrest, thereby uncoupling G 2 arrest from lethality. Thus, MMR-dependent intrinsic apoptosis is p53-independent, but stimulated by hMLH1/c-Abl/p73␣/GADD45␣ retrograde signaling.

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Section: Discussionmentioning

confidence: 77%

DNA Mismatch Repair-dependent Activation of c-Abl/p73α/GADD45α-mediated Apoptosis

Morales

Hwang

et al. 2008

Journal of Biological Chemistry

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“…These findings indicate that PKCδ may be potentially correlated with neuronal degeneration in Parkinson's disease. Besides, some reports have suggested that the activation of PKCδ mediates the cytotoxic effects of the oxidative stress responses [18,20,21] induced by ultraviolet radiation [22] or environmental neurotoxins (such as MPP + and MMT) in dopaminergic neurons [1][2][3][4]23,24] .…”

Section: Discussionmentioning

confidence: 99%

Rottlerin protected dopaminergic cell line from cytotoxicity of 6-hydroxydopamine by inhibiting PKCδ phosphorylation

et al. 2009

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Objective The present study aims to investigate the role of protein kinase C δ subtype (PKCδ) phosphorylation in the process of 6-hydroxydopamine (6-OHDA)-induced dopaminergic cell death, and demonstrate the molecular basis of neurological disorders, such as Parkinson's disease. Methods The pheochromocytoma (PC12) cell line was employed in the present study. Cells were treated with 2 μmol/L PKCδ inhibitor Rottlerin, 10 nmol/L protein kinase C α subtype (PKCα) inhibitor bisindolylmaleimide I, or 5 nmol/L Gö6976 that could specifically inhibit the calcium-dependent PKC isoforms, respectively. PKCδ activator phorbol-12-myristate-13-acetate (PMA, 100 nmol/L) was also used in this study. All these agents were added to the medium before cells were incubated with 6-OHDA. Cells with no treatment served as control. The cytotoxicity of 6-OHDA was determined by methyl thiazolyl tetrazolium (MTT) reduction assay and PKCδ phosphorylation levels in various groups were measured by western blotting. Results Bisindolylmaleimide I and Gö6976 exerted no significant attenuation on the cytotoxicity of 6-OHDA, nor any effects on PKCδ phosphorylation in PC12 cells. However, Rottlerin could inhibit the phosphorylation of PKCδ and attenuate 6-OHDA-induced cell death, and the cell viability was raised to 69.6±2.63% of that in control group (P < 0.05). In contrast, PMA induced a significant increase in PKCδ phosphorylation and also strengthened the cytotoxic effects of 6-OHDA. The cell viability of PMA-treated PC12 cells decreased to 49.8±5.06% of that in control group (P < 0.001). Conclusion Rottlerin can protect PC12 cells from cytotoxicity of 6-OHDA probably by inhibiting PKCδ phosphorylation. The results suggest that PKCδ may be a key regulator of neuron loss in Parkinson's disease.

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“…Both forms of the c-Abl are activated by genotoxic stresses, including oxidative damage (Sun et al, 2000a,b), with activation being associated with cell death. In the case of hydrogen peroxide, PKCd (Sun et al, 2000b) is believed to mediate activation of nuclear c-Abl, targeting it to the mitochondria where it takes part in initiating apoptosis (Kumar et al, 2001). Accordingly, cells deficient in c-Abl show attenuated cytochrome C release and reduced apoptosis in response to hydrogen peroxide treatment (Sun et al, 2000a).…”

Section: Other Signaling Molecules and Pathways Jak/stat Pathwaymentioning

confidence: 99%

Cellular response to oxidative stress: Signaling for suicide and survival*

Martindale

Holbrook

2002

Journal Cellular Physiology

2,100

1,596

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Reactive oxygen species (ROS), whether produced endogenously as a consequence of normal cell functions or derived from external sources, pose a constant threat to cells living in an aerobic environment as they can result in severe damage to DNA, protein, and lipids. The importance of oxidative damage to the pathogenesis of many diseases as well as to degenerative processes of aging has becoming increasingly apparent over the past few years. Cells contain a number of antioxidant defenses to minimize fluctuations in ROS, but ROS generation often exceeds the cell's antioxidant capacity, resulting in a condition termed oxidative stress. Host survival depends upon the ability of cells and tissues to adapt to or resist the stress, and repair or remove damaged molecules or cells. Numerous stress response mechanisms have evolved for these purposes, and they are rapidly activated in response to oxidative insults. Some of the pathways are preferentially linked to enhanced survival, while others are more frequently associated with cell death. Still others have been implicated in both extremes depending on the particular circumstances. In this review, we discuss the various signaling pathways known to be activated in response to oxidative stress in mammalian cells, the mechanisms leading to their activation, and their roles in influencing cell survival. These pathways constitute important avenues for therapeutic interventions aimed at limiting oxidative damage or attenuating its sequelae. Published 2002 Wiley‐Liss, Inc.

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Targeting of the c-Abl Tyrosine Kinase to Mitochondria in the Necrotic Cell Death Response to Oxidative Stress

Cited by 101 publications

References 28 publications

DNA Mismatch Repair-dependent Activation of c-Abl/p73α/GADD45α-mediated Apoptosis

DNA Mismatch Repair-dependent Activation of c-Abl/p73α/GADD45α-mediated Apoptosis

Rottlerin protected dopaminergic cell line from cytotoxicity of 6-hydroxydopamine by inhibiting PKCδ phosphorylation

Cellular response to oxidative stress: Signaling for suicide and survival*

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