Arsenic Trioxide Augments Chk2/p53-mediated Apoptosis by Inhibiting Oncogenic Wip1 Phosphatase

Yoda, Akinori; Toyoshima, Kyoko; Watanabe, Yasuhide; Onishi, Nobuyuki; Hazaka, Yuki; Tsukuda, Yusuke; Tsukada, Junichi; Kondo, Takeshi; Tanaka, Yoshiya; Minami, Yasuhiro

doi:10.1074/jbc.m800560200

Cited by 53 publications

(47 citation statements)

References 55 publications

(39 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Thus, we concluded that PML was dispensable for the anti-HCV activity of ATO. Since the Chk2 checkpoint kinase has recently been implicated in ATO-induced apoptosis and in association with PML (27,63,64,66), we examined the anti-HCV activity in the ATO-treated Chk2 knockdown O cells (3). As we previously described, Western blot analysis demonstrated very effective knockdown of Chk2 in O cells (Fig.…”

Section: Resultsmentioning

confidence: 99%

Arsenic Trioxide Inhibits Hepatitis C Virus RNA Replication through Modulation of the Glutathione Redox System and Oxidative Stress

Kuroki

Ariumi

Ikeda

et al. 2009

J Virol

View full text Add to dashboard Cite

Arsenic trioxide (ATO), a therapeutic reagent used for the treatment of acute promyelocytic leukemia, has recently been reported to increase human immunodeficiency virus type 1 infectivity. However, in this study, we have demonstrated that replication of genome-length hepatitis C virus (HCV) RNA (O strain of genotype 1b) was notably inhibited by ATO at submicromolar concentrations without cell toxicity. RNA replication of HCV-JFH1 (genotype 2a) and the release of core protein into the culture supernatants were also inhibited by ATO after the HCV infection. To clarify the mechanism of the anti-HCV activity of ATO, we examined whether or not PML is associated with this anti-HCV activity, since PML is known to be a target of ATO. Interestingly, we observed the cytoplasmic translocation of PML after treatment with ATO. However, ATO still inhibited the HCV RNA replication even in the PML knockdown cells, suggesting that PML is dispensable for the anti-HCV activity of ATO. In contrast, we found that N-acetyl-cysteine, an antioxidant and glutathione precursor, completely and partially eliminated the anti-HCV activity of ATO after 24 h and 72 h of treatment, respectively. In this context, it is worth noting that we found an elevation of intracellular superoxide anion radical, but not hydrogen peroxide, and the depletion of intracellular glutathione in the ATO-treated cells. Taken together, these findings suggest that ATO inhibits the HCV RNA replication through modulation of the glutathione redox system and oxidative stress.Hepatitis C virus (HCV) is the causative agent of chronic hepatitis, which progresses to liver cirrhosis and hepatocellular carcinoma. HCV is an enveloped virus with a positive singlestranded 9.6-kb RNA genome, which encodes a large polyprotein precursor of approximately 3,000 amino acid residues. This polyprotein is cleaved by a combination of the host and viral proteases into at least 10 proteins in the following order: core, envelope 1 (E1), E2, p7, nonstructural 2 (NS2), NS3, NS4A, NS4B, NS5A, and NS5B (30).Alpha interferon has been used as an effective anti-HCV reagent in clinical therapy for patients with chronic hepatitis C. The current combination treatment with pegylated alpha interferon and ribavirin, a nucleoside analogue, has been shown to improve the sustained virological response rate to more than 50% (15). However, the adverse effects of the combination therapy and the limited efficacy against genotype 1b warrant the development of new anti-HCV reagents.Arsenic trioxide (ATO) (As 2 O 3 , arsenite) has been used as a therapeutic reagent in acute promyelocytic leukemia, which bears an oncogenic PML-retinoic acid receptor alpha fusion protein resulting from chromosomal translocation (51,52,68,70). The ATO treatment induces complete remission through degradation of the aberrant PML-retinoic acid receptor ␣ (70). The PML tumor suppressor protein is required for formation of the PML nuclear body (PML-NB), also known as nuclear dot 10 or the PML oncogenic domain, which is often disrupted by i...

show abstract

Section: Resultsmentioning

confidence: 99%

Arsenic Trioxide Inhibits Hepatitis C Virus RNA Replication through Modulation of the Glutathione Redox System and Oxidative Stress

Kuroki

Ariumi

Ikeda

et al. 2009

J Virol

View full text Add to dashboard Cite

show abstract

“…We also assessed HR-and NHEJ-mediated DSB repair in LB4 and TNeo99-7 cells in which WIP1 levels were inhibited by WIP1 shRNA vectors and two known WIP1 inhibitors, arsenic trioxide and CCCT007093 (53,54). Introduction of I-SceI into all three categories of WIP1-depleted LB4 and TNeo99-7 cells consistently resulted in increased recombination frequency compared with I-SceI-containing control cells with normal WIP1 levels (Fig.…”

Section: Wip1 Inhibits Recruitment Of Mdc1 and 53bp1 To Damagementioning

confidence: 99%

Wild-type p53-induced Phosphatase 1 Dephosphorylates Histone Variant γ-H2AX and Suppresses DNA Double Strand Break Repair

Moon

Lin

Zhang

et al. 2010

Journal of Biological Chemistry

View full text Add to dashboard Cite

In response to DNA double strand breaks, the histone variant H2AX at the break site is phosphorylated at serine 139 by DNA damage sensor kinases such as ataxia telangiectasia-mutated, forming ␥-H2AX. This phosphorylation event is critical for sustained recruitment of other proteins to repair the break. After repair, restoration of the cell to a prestress state is associated with ␥-H2AX dephosphorylation and dissolution of ␥-H2AX-associated damage foci. The phosphatases PP2A and PP4 have previously been shown to dephosphorylate ␥-H2AX. Here, we demonstrate that the wild-type p53-induced phosphatase 1 (WIP1) also dephosphorylates ␥-H2AX at serine 139 in vitro and in vivo. Overexpression of WIP1 reduces formation of ␥-H2AX foci in response to ionizing and ultraviolet radiation and blocks recruitment of MDC1 (mediator of DNA damage checkpoint 1) and 53BP1 (p53 binding protein 1) to DNA damage foci. Finally, these inhibitory effects of WIP1 on ␥-H2AX are accompanied by WIP1 suppression of DNA double strand break repair. Thus, WIP1 has a homeostatic role in reversing the effects of ataxia telangiectasia-mutated phosphorylation of H2AX.

show abstract

“…Thus chemotherapeutic agents activating p53 beyond its growtharresting function should be considered as an aid to p53 protein stabilizers such as blockers of MDM2 function (Hasegawa et al, 2009). Among these regulators, WIP1 phosphatase (PPM1D), a p53 target and negative loop of autoregulation of p53 was suggested as a possibility, however, not tested in T-ALL (Lu et al, 2008;Yoda et al, 2008). Even though the Ser46 phosphorylated form of p53 was shown to associate with apoptotic activity, point mutation substituting this amino acid to alanine did not prevent activation of p53 apoptotic function (Kurihara et al, 2007).…”

Section: Resultsmentioning

confidence: 99%

p53 as a Therapeutic Target in T-ALL

Riz¹,

Yang²,

Peng³

et al. 2011

Novel Aspects in Acute Lymphoblastic Leukemia

View full text Add to dashboard Cite

Arsenic Trioxide Augments Chk2/p53-mediated Apoptosis by Inhibiting Oncogenic Wip1 Phosphatase

Cited by 53 publications

References 55 publications

Arsenic Trioxide Inhibits Hepatitis C Virus RNA Replication through Modulation of the Glutathione Redox System and Oxidative Stress

Arsenic Trioxide Inhibits Hepatitis C Virus RNA Replication through Modulation of the Glutathione Redox System and Oxidative Stress

Wild-type p53-induced Phosphatase 1 Dephosphorylates Histone Variant γ-H2AX and Suppresses DNA Double Strand Break Repair

p53 as a Therapeutic Target in T-ALL

Contact Info

Product

Resources

About