ATR, PML, and CHK2 play a role in arsenic trioxide-induced apoptosis
ATR, PML, and CHK2 play a role in arsenic trioxide-induced apoptosis
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DOI：
10.1074/jbc.m604392200
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发表时间：
2006-09-29
影响因子：
4.8
通讯作者：
Kim, Myung K.
中科院分区：
文献类型：
--
作者：
Joe, YeonSoo;Jeong, Jae-Hoon;Kim, Myung K.
三氧化二砷（ATO）是一种有效的抗白血病化疗药物，用于治疗急性早幼粒细胞白血病（APL），APL是由t（15，17）染色体易位产生PML-RAR α，一种肿瘤抑制因子PML和维甲酸受体RAR α之间的融合蛋白。APL患者最初用维甲酸治疗，但大多数发展为耐药性和复发。相反，ATO诱导长期缓解，即使在复发的情况下。然而，ATO杀死白血病细胞的分子机制尚未完全了解。我们发现，ATO诱导细胞凋亡，至少部分，通过激活促凋亡激酶Chk 2。ATO通过刺激ATR（共济失调毛细血管扩张突变和Rad 3相关）激酶（一种Chk 2激活激酶）来实现这一点。同时，ATO降解PML-RAR α，导致PML的恢复，这是自磷酸化和Chk 2完全激活所必需的。结果，p53依赖性凋亡途径被激活。基于此，我们认为ATR、PML、Chk 2和p53组成的通路在ATO介导的细胞凋亡中起作用，这一观点与Chk 2基因完整且p53基因突变在APL中极为罕见的观察结果一致。
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 alpha, a fusion protein between a tumor suppressor PML and the retinoic acid receptor RAR alpha. 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 alpha, 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.