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

• Published in: The Journal of biological chemistry 2006-09, Vol.281 (39), p.28764-28771
• Main Authors: Joe, YeonSoo, Jeong, Jae-Hoon, Yang, Shutong, Kang, Hyeog, Motoyama, Noburu, Pandolfi, Pier Paolo, Chung, Jay H., Kim, Myung K.
• Format: Article
• Language: English
• Subjects: Animals; Antineoplastic Agents - pharmacology; Apoptosis; Arsenic Trioxide; Arsenicals - pharmacology; Ataxia Telangiectasia Mutated Proteins; Cell Cycle Proteins - physiology; Cell Line; Checkpoint Kinase 2; Enzyme Activation; Fibroblasts - metabolism; Mice; Mice, SCID; Mice, Transgenic; Nuclear Proteins - physiology; Oxides - pharmacology; Promyelocytic Leukemia Protein; Protein-Serine-Threonine Kinases - physiology; Transcription Factors - physiology; Tumor Suppressor Protein p53 - metabolism; Tumor Suppressor Proteins - physiology
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M604392200

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-RARα, a fusion protein between a tumor suppressor PML and the retinoic acid receptor RARα. 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-RARα, 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.