Intrinsic Kinase Activity and SQ/TQ Domain of Chk2 Kinase as Well as N-terminal Domain of Wip1 Phosphatase Are Required for Regulation of Chk2 by Wip1

Yoda, Akinori; Xu, Xiao Zhou; Onishi, Nobuyuki; Toyoshima, Kyoko; Fujimoto, Hiroko; Kato, Naoko; Oishi, Isao; Kondo, Takeshi; Minami, Yasuhiro

doi:10.1074/jbc.m600403200

Cited by 50 publications

(51 citation statements)

References 55 publications

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“…PPM1D activation results in negative regulation of P53 function and other tumour suppressor pathways by selective inactivation of P38 kinase (Fiscella et al, 1997;Takekawa et al, 2000;Bulavin et al, 2004). Additional functions for PPM1D include the regulation of the base excision pathway of DNA repair (Lu et al, 2004), progesterone receptor function (Proia et al, 2006), the homoeostatic regulation of the checkpoint kinases CHK1 and CHK2 (Lu et al, 2005;Fujimoto et al, 2006;Nannenga et al, 2006;OlivaTrastoy et al, 2006;Yoda et al, 2006;Yu et al, 2006) and the activation of ataxia-telangiectasia mutated (Shreeram et al, 2006), all of which may also contribute to the oncogenic effects of PPM1D overexpression. Mice deficient in Ppm1d are viable, with only minor defects in immune function and spermatogenesis (Choi et al, 2002).…”

Section: Introductionmentioning

confidence: 99%

A chemical inhibitor of PPM1D that selectively kills cells overexpressing PPM1D

et al. 2007

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The PPM1D gene is aberrantly amplified in a range of common cancers and encodes a protein phosphatase that is a potential therapeutic target. However, the issue of whether inhibition of PPM1D in human tumour cells that overexpress this protein compromises their viability has not yet been fully addressed. We show here, using an RNA interference (RNAi) approach, that inhibition of PPM1D can indeed reduce the viability of human tumour cells and that this effect is selective; tumour cell lines that overexpress PPM1D are sensitive to PPM1D inhibition whereas cell lines with normal levels are not. Loss of viability associated with PPM1D RNAi in human tumour cells occurs via the activation of the kinase P38. To identify chemical inhibitors of PPM1D, a high-throughput screening of a library of small molecules was performed. This strategy successfully identified a compound that selectively reduces viability of human tumour cell lines that overexpress PPM1D. As expected of a specific inhibitor, the toxicity to PPM1D overexpressing cell lines after inhibitor treatment is P38 dependent. These results further validate PPM1D as a therapeutic target and identify a proof-of-principle small molecule inhibitor.

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Section: Introductionmentioning

confidence: 99%

A chemical inhibitor of PPM1D that selectively kills cells overexpressing PPM1D

et al. 2007

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“…Wip1 is another phosphatase critically involved in recovery from the DNA damage checkpoint; its expression level and association with DDR factors increase after DNA damage, and results in their dephosphorylation (Lu et al, 2007). The N-terminal SQ/TQ region of Chk2 that interacts with Wip1 was also found to inhibit Wip1 phosphatase activity in vitro (Yoda et al, 2006), raising an interesting possibility that mutual regulation between Wip1 and Chk2, or perhaps also between Wip1 and other substrates, takes place in the DDR, particularly in making the vital decision of whether to sustain checkpoint arrest or initiate recovery from it.…”

Section: Regulation Of the Ddr Phosphatases By Dna Damagementioning

confidence: 99%

“…Similar to Ptc2 and Ptc3 in yeast, human Wip1 associates with Chk2 and dephosphorylates Chk2 at Thr 68 Yoda et al, 2006;OlivaTrastoy et al, 2007). However, distinct from the case with Ptc2 and Rad53 in yeast, interaction between Wip1 and Chk2 is mediated through the N-terminal SQ/TQ region in Chk2 and an N-terminal domain in Wip1 (Yoda et al, 2006; Figure 2d). …”

Section: Protein Phosphatase-dependent Regulation Of Chk1mentioning

confidence: 99%

Serine/threonine phosphatases in the DNA damage response and cancer

Peng

Maller

2010

Oncogene

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The cellular response to DNA damage is a crucial surveillance mechanism that maintains genomic integrity and prevents cancer progression. Previous studies identified multiple Ser/Thr protein kinases that have pivotal roles in the activation of this response. It is interesting that a growing body of evidence suggests that these kinases and their substrates are under tight modulation by numerous Ser/Thr phosphatases. In this study, we review recent reports that reveal new functions and regulation of these phosphatases. Similar to the kinases in this pathway, phosphatases may also be intimately involved in cancer progression and present valuable targets for cancer therapy.

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“…This is achieved by the regulation of the ataxia talengiectasia mutated (ATM) and Rad3 related (ATR) and p53 pathways. PPM1D directly dephosphorylates ATM [19,20] and its downstream target checkpoint kinase 2 (Chk2; Thr 68 ) [21][22][23], significantly reducing their activities. Although PPM1D has not been shown to target ATR directly, it does dephosphorylate downstream targets of ATR.…”

Section: Introductionmentioning

confidence: 99%

Akt confers cisplatin chemoresistance in human gynecological carcinoma cells by modulating PPM1D stability

Alayoud¹,

Kim²,

Pelletier

et al. 2014

Molecular Carcinogenesis

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Ovarian cancer (OVCA) and cervical cancer (CECA) are lethal gynecological malignancies. Cisplatin (CDDP) and platinum derivatives are first line chemotherapeutics and their resistance impedes successful treatment. Understanding the molecular dysregulation underlying chemoresistance is important in developing rational therapeutic strategies. We have established that Protein Phosphatase Magnesium-dependent 1 D (PPM1D) confers CDDP resistance in gynecological cancer cells by deactivating p53. However, whether CDDP regulates intra-cellular PPM1D localization and whether this regulation is different between chemosensitive and chemoresistant cancer cells is unknown. Moreover, whether Akt regulates PPM1D in the context of CDDP resistance has not been studied. To illustrate the role of PPM1D in gynecological cancer cell chemoresistance and its regulation by Akt we have demonstrated that: (a) CDDP induced PPM1D downregulation through proteasomal degradation in sensitive CECA cells; (b) CDDP induced PPM1D nuclear localization in resistant CECA cells, and nuclear exclusion in sensitive CECA cells and OVCA xenografts; (c) Over-expression of active Akt in sensitive CECA cells stabilized PPM1D content through inhibition of CDDP-induced PPM1D down-regulation; (d) Inhibition of Akt activity in resistant OVCA cells leads to decreased PPM1D stability and CDDP-induced down-regulation in resistant CECA cells; and (e) PPM1D is highly expressed in human ovarian tumor subtypes and in a tissue microarray panel of human ovarian tumors. In conclusion, we have established that PPM1D plays an important role in promoting CDDP resistance and as a novel downstream target of Akt, PPM1D mediates its action in conferring CDDP resistance in gynecological cancer cells. © 2014 The Authors. Molecular Carcinogenesis published by Wiley Periodicals, Inc.Key words: cisplatin chemoresistance; ovarian cancer; PPM1D; Akt; apoptosis INTRODUCTIONOvarian cancer (OVCA) and cervical cancer (CECA) are the most lethal gynecological malignancies. Although OVCA ranks first in the number of deaths each year, due primarily to its late diagnosis and the development of chemoresistance [1], CECA is more frequent and less deadly due to early detection. Surgical de-bulking of the tumor mass followed by adjuvant chemotherapy is the conventional course of therapy for OVCA, whereas a combination of radiation and chemotherapy is the preferred treatment regimen for CECA. Platinum derivatives, including Cisplatin (CDDP; cis-diamminedichloroplatinum) in combination with paclitaxel, are first-line chemotherapeutic agents in the treatment of these gynecologic cancers. CDDP induces apoptosis by creating inter-and intra-strand DNA adducts through irreversible intercalation, thereby inducing both the DNA damage and the apoptotic responses [2]. The majority of patients respond to chemotherapy at first, however, recurrence of the disease is a common event and tumors are usually more aggressive, metastasize to secondary target tissues, and acquire resistance to conventional chemotherape...

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Intrinsic Kinase Activity and SQ/TQ Domain of Chk2 Kinase as Well as N-terminal Domain of Wip1 Phosphatase Are Required for Regulation of Chk2 by Wip1

Cited by 50 publications

References 55 publications

A chemical inhibitor of PPM1D that selectively kills cells overexpressing PPM1D

A chemical inhibitor of PPM1D that selectively kills cells overexpressing PPM1D

Serine/threonine phosphatases in the DNA damage response and cancer

Akt confers cisplatin chemoresistance in human gynecological carcinoma cells by modulating PPM1D stability

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