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J. Biol. Chem., Vol. 283, Issue 27, 18969-18979, July 4, 2008

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

Akinori Yoda, Kyoko Toyoshima, Yasuhide Watanabe, Nobuyuki Onishi¹, Yuki Hazaka, Yusuke Tsukuda, Junichi Tsukada, Takeshi Kondo^¶, Yoshiya Tanaka^||, and Yasuhiro Minami²

From the Department of Physiology and Cell Biology, Faculty of Medical Sciences, Graduate School of Medicine, Kobe University, 7-5-1, Kusunoki-cho, Chuo-ku, Kobe 650-0017, Japan, the Cancer Chemotherapy Center and ^||First Department of Internal Medicine, School of Medicine, University of Occupational and Environmental Health, 1-1, Iseigaoka, Yahatanishi-ku, Kitakyushu 807-8555, Japan, and the ^¶Department of Gastroenterology and Hematology, Graduate School of Medicine, Hokkaido University, Kita 15 Nishi 7, Kita-ku, Sapporo, Hokkaido 060-8638, Japan

The oncogenic Wip1 phosphatase (PPM1D) is induced upon DNA damage in a p53-dependent manner and is required for inactivation or suppression of DNA damage-induced cell cycle checkpoint arrest and of apoptosis by dephosphorylating and inactivating phosphorylated Chk2, Chk1, and ATM kinases. It has been reported that arsenic trioxide (ATO), a potent cancer chemotherapeutic agent, in particular for acute promyelocytic leukemia, activates the Chk2/p53 pathway, leading to apoptosis. ATO is also known to activate the p38 MAPK/p53 pathway. Here we show that phosphatase activities of purified Wip1 toward phosphorylated Chk2 and p38 in vitro are inhibited by ATO in a dose-dependent manner. Furthermore, DNA damage-induced phosphorylation of Chk2 and p38 in cultured cells is suppressed by ectopic expression of Wip1, and this Wip1-mediated suppression can be restored by the presence of ATO. We also show that treatment of acute promyelocytic leukemia cells with ATO resulted in induction of phosphorylation and activation of Chk2 and p38 MAPK, which are required for ATO-induced apoptosis. Importantly, this ATO-induced activation of Chk2/p53 and p38 MAPK/p53 apoptotic pathways can be enhanced by siRNA-mediated suppression of Wip1 expression, further indicating that ATO inhibits Wip1 phosphatase in vivo. These results exemplify that Wip1 is a direct molecular target of ATO.

Received for publication, January 23, 2008 , and in revised form, May 2, 2008.

^* This work was supported by a grant-in-aid for scientific research in priority areas (to Y. M.), a grant-in-aid for young scientists (B) (to A. Y.), a grant from the 21st Century Centers of Excellence Program "Center of Excellence for Signal Transduction Disease: Diabetes Mellitus as Model" (to Y. M.) from the Ministry of Education, Culture, Sports, Science, and Technology of Japan, and by Daiichi Sankyo Pharmaceutical Co., Ltd. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. S1–S4.

¹ Research fellow of the Japan Society for the Promotion of Sciences.

² To whom correspondence should be addressed. Tel.: 81-78-382-5560; Fax: 81-78-382-5579; E-mail: minami{at}kobe-u.ac.jp.

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