ATR, PML, and CHK2 play a role in arsenic trioxide-induced apoptosis Journal Article
| Authors: | Joe, Y.; Jeong, J. H.; Yang, S.; Kang, H.; Motoyama, N.; Pandolfi, P. P.; Chung, J. H.; Kim, M. K. |
| Article Title: | ATR, PML, and CHK2 play a role in arsenic trioxide-induced apoptosis |
| Abstract: | 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. |
| Keywords: | controlled study; nonhuman; antineoplastic agents; proteins; animal cell; mouse; animals; cell cycle proteins; mice; apoptosis; protein degradation; cell line; enzyme activation; mice, scid; autophosphorylation; oncology; protein p53; mice, transgenic; transcription factors; nuclear proteins; arsenic trioxide; arsenicals; oxides; enzyme phosphorylation; drug mechanism; genetic engineering; protein-serine-threonine kinases; tumor suppressor proteins; fibroblasts; tumor suppressor protein p53; checkpoint kinase 2; molecular biology; drug therapy; patient treatment; atr protein; retinoic acid; enzyme induction; ataxia telangiectasia; promyelocytic leukemia protein; retinoic acid receptor alpha; cells; acute promyelocytic leukemia (apl); activation analysis; ataxia telangiectasia (atr) |
| Journal Title: | Journal of Biological Chemistry |
| Volume: | 281 |
| Issue: | 39 |
| ISSN: | 0021-9258 |
| Publisher: | American Society for Biochemistry and Molecular Biology |
| Date Published: | 2006-09-29 |
| Start Page: | 28764 |
| End Page: | 28771 |
| Language: | English |
| DOI: | 10.1074/jbc.M604392200 |
| PUBMED: | 16891316 |
| PROVIDER: | scopus |
| DOI/URL: | |
| Notes: | --- - "Cited By (since 1996): 20" - "Export Date: 4 June 2012" - "CODEN: JBCHA" - "Source: Scopus" |
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