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J. Biol. Chem., Vol. 281, Issue 39, 28764-28771, September 29, 2006

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ATR, PML, and CHK2 Play a Role in Arsenic Trioxide-induced Apoptosis^*

YeonSoo Joe, Jae-Hoon Jeong, Shutong Yang, Hyeog Kang, Noburu Motoyama, Pier Paolo Pandolfi^¶, Jay H. Chung¹, and Myung K. Kim²

From the Laboratory of Biochemical Genetics, NHLBI, National Institutes of Health, Bethesda, Maryland 20892, Department of Geriatric Research, National Institute for Longevity Sciences, 36-3 Gengo, Morioka, Obu, Aichi 474-8522, Japan, and ^¶Cancer Biology and Genetics Program and Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, New York 10021

Arsenic trioxide (ATO) is a potent anti-leukemic chemotherapeutic agent for acute promyelocytic leukemia (APL) that results from a t (15, 17) chromosomal translocation that produces PML-RAR, a fusion protein between a tumor suppressor PML and the retinoic acid receptor RAR. APL patients are initially treated with retinoic acid, but most develop resistance and relapse. In contrast, ATO induces prolonged remissions even in the relapsed cases. However, the molecular mechanisms by which ATO kills the leukemic cells are not fully understood. We find that ATO induces apoptosis, at least in part, by activating proapoptotic kinase Chk2. ATO does this by stimulating ATR (ataxia telangiectasia mutated and Rad3-related) kinase, a Chk2-activating kinase. In conjunction, ATO degrades PML-RAR, resulting in the restoration of PML, which is required for autophosphorylation and full activation of Chk2. As a result, the p53-dependent apoptosis pathway is activated. Based on this, we propose that a pathway composed of ATR, PML, Chk2, and p53 plays a role in ATO-mediated apoptosis, a notion that is consistent with the observation that Chk2 is genetically intact and mutations in the p53 gene are extremely rare in APL.

Received for publication, May 8, 2006 , and in revised form, August 1, 2006.

^* This work was supported by the Intramural Research Program of the NHLBI, National Institutes of Health. 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 Fig. S1.

¹ To whom correspondence may be addressed: Bldg. 10, Rm. 7D14, Laboratory of Biochemical Genetics, NHLBI, National Institutes of Health, 10 Center Dr., Bethesda, MD 20892. Tel.: 301-496-3075; Fax: 301-480-4557; E-mail: ChungJ{at}nhlbi.nih.gov. ² To whom correspondence may be addressed: Bldg. 10, Rm. 7D18, Laboratory of Biochemical Genetics, NHLBI, National Institutes of Health, 10 Center Dr., Bethesda, MD 20892. Tel.: 301-451-3448; Fax: 301-480-4557; E-mail: KimM{at}nhlbi.nih.gov.

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