Reactive Oxygen Species-induced Phosphorylation of p53 on Serine 20 Is Mediated in Part by Polo-like Kinase-3

Xie, Suqing; Wang, Qi; Wu, Huiyun; Cogswell, John; Luo, Lu; Jhanwar‐Uniyal, Meena; Dai, Wei

doi:10.1074/jbc.m104157200

Cited by 135 publications

(129 citation statements)

References 41 publications

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“…We have recently observed that exposure of cancer cells to a-TOS results in early generation of reactive oxygen species (ROS) (Weber et al, 2003), and we have also observed phosphorylation of p53 (Tomasetti et al, unpublished data). It is thus feasible that a p53-mediated process contributes to a-TOS-induced DR5 upregulation in MM cells, consistent with another report suggesting p53 activation as a mode of sensitisation of cancer cells towards TRAIL killing (Xie et al, 2001). Although Met-5A cells, used here as a control cell line, are immortalised with SV-40 resulting in inactivation of p53, translocation of p53 into the nucleus was also observed in these cells following a-TOS treatment (unpublished data).…”

Section: Discussionsupporting

confidence: 89%

α-Tocopheryl succinate and TRAIL selectively synergise in induction of apoptosis in human malignant mesothelioma cells

Tomasetti¹,

Rippo²,

Alleva

et al. 2004

Br J Cancer

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Malignant mesothelioma (MM) is a fatal type of neoplasia with poor therapeutic prognosis, largely due to resistance to apoptosis. We investigated the apoptotic effect of a-tocopheryl succinate (a-TOS), a strong proapoptotic agent, in combination with the immunological apoptogen TNF-related apoptosis-inducing ligand (TRAIL) on both MM and nonmalignant mesothelial cells, since MM cells show low susceptibility to the clinically intriguing TRAIL. All MM cell lines tested were sensitive to a-TOS-induced apoptosis, and exerted high sensitivity to TRAIL in the presence of subapoptotic doses of the vitamin E analogue. Neither TRAIL or a-TOS alone or in combination caused apoptosis in nonmalignant mesothelial cells. Isobologram analysis of the cytotoxicity assays revealed a synergistic interaction between the two agents in MM cells and their antagonistic effect in nonmalignant mesothelial cells. TRAILinduced apoptosis and its augmentation by a-TOS were inhibited by the caspase-8 inhibitor Z-IETD-FMK and the pan-caspase inhibitor Z-VAD-FMK. Activation of caspase-8 was required to induce apoptosis, which was amplified by a-TOS via cytochrome c release following Bid cleavage, with ensuing activation of caspase-9. Enhancement of TRAIL-induced apoptosis in MM cells by a-TOS was also associated with upregulation of the TRAIL cognate death receptors DR4 and DR5. Our results show that a-TOS and TRAIL act in synergism to kill MM cells via mitochondrial pathway, and are nontoxic to nonmalignant mesothelial cells. These findings are indicative of a novel strategy for treatment of thus far fatal MM.

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Section: Discussionsupporting

confidence: 89%

α-Tocopheryl succinate and TRAIL selectively synergise in induction of apoptosis in human malignant mesothelioma cells

Tomasetti¹,

Rippo²,

Alleva

et al. 2004

Br J Cancer

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“…It is the loss of these critical p53-dependent checkpoint functions that is believed to render AT cells hypersensitive to IR. A recent report showed that the hydrogen peroxideinduced phosphorylation of p53 on multiple serine residues was blocked in ATMÀ/À cells (Xie et al, 2001). Specifically, serine-20 of p53 was phosphorylated by polo-like kinase-3 (Plk3) which demonstrated hydrogen peroxide-induced activity dependent also on ATM function.…”

Section: Ataxia-telangiectasia Mutated (Atm) Kinasementioning

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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“…Respiratory inhibitors produce reactive oxygen species in mitochondria. 42 Reactive oxygen species 43,44 and generators of reactive oxygen species 45,46 have been reported to activate p53. However, reactive oxygen species phosphorylate serines 15 and 20.…”

Section: Discussionmentioning

confidence: 99%

“…However, reactive oxygen species phosphorylate serines 15 and 20. 43,44 Respiratory inhibitors that specifically induce phosphorylation of serine 392 without affecting serines 15 and 20 might act by means of a distinct pathway of p53 activation.…”

Section: Discussionmentioning

confidence: 99%

Ascochlorin activates p53 in a manner distinct from DNA damaging agents

Jeong

Nakajima

Magae

et al. 2009

Intl Journal of Cancer

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Ascochlorin, a prenylphenol antitumor antibiotic, profoundly increases the expression of endogenous p53 by increasing protein stability in the human osteosarcoma cells and human colon cancer cells. Ascochlorin also increases DNA binding activity to the p53 consensus sequence in nuclear extract and enhances transcription of p53 downstream targets. Ascochlorin specifically induces p53 phosphorylation at ser 392 without affecting ser 15 or 20, whereas DNA damaging agents typically phosphorylate these serines. Moreover, ascochlorin does not induce phosphorylation of ATM and CHK1, an established substrate of ATR that is activated by genotoxins, nor does it increase DNA strand break, as confirmed by comet assay. The structure-activity relationship suggests that p53 activation by ascochlorin is related to inhibition of mitochondrial respiration, which is further supported by the observation that respiratory inhibitors activate p53 in a manner similar to ascochlorin. These results suggest that ascochlorin, through the inhibition of mitochondrial respiration, activates p53 through a mechanism distinct from genotoxins. ' UICCKey words: AP-1; p53; mitochondrial respiration; ascochlorin; ATM; ATR Ascochlorin and ascofuranone ( Fig. 1) are prenylphenol antifungal antibiotics isolated from an incomplete fungus, Ascochyta viciae. Although originally reported to be an antiviral antibiotic, 1-3 ascochlorin and its derivatives exhibit a large variety of physiological activities including hypolipidemic activity, 2 suppression of hypertension, 4 amelioration of types I and II diabetes, 5,6 immunomodulation 7 and antitumor activity. 8,9 Ascochlorin and ascofuranone, one of its derivatives, inhibit oxidative phosphorylation by hindering ubiquinone-dependent electron transport in isolated mitochondria, 10-12 and it has been suggested that the antiviral activity of ascochlorin and macrophage activation by ascofuranone are a result of this inhibitory activity on mitochondrial respiration. 10,11,13 These compounds also modulate the activity of nuclear hormone receptors, 14 which suggests that mechanisms other than those involving the respiratory chain contribute to their physiological activities.Ascochlorin-related compounds show profound antitumor activity against a variety of transplantable tumors and suppress the metastasis of melanomas and lung carcinomas in murine animal models. 8,9 Because pretreatment with ascofuranone before tumor implantation is as effective as treatment after tumor implantation, the antitumor activity of ascofuranone must be mediated, at least in part, by activation of a host defense mechanism against tumors. We recently found that ascochlorin and ascofuranone selectively suppress the AP-1 activity of human renal carcinoma cells, as well as its downstream targets such as matrix metalloproteinase-9, through suppression of the Erk1/2 signaling pathway, 15,16 suggesting that ascochlorin directly suppresses tumor malignancy by this mechanism. We also found that human breast cancer cell lines that are devoid of es...

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Reactive Oxygen Species-induced Phosphorylation of p53 on Serine 20 Is Mediated in Part by Polo-like Kinase-3

Cited by 135 publications

References 41 publications

α-Tocopheryl succinate and TRAIL selectively synergise in induction of apoptosis in human malignant mesothelioma cells

α-Tocopheryl succinate and TRAIL selectively synergise in induction of apoptosis in human malignant mesothelioma cells

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

Ascochlorin activates p53 in a manner distinct from DNA damaging agents

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