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• W2385011293 abstract "// Wataru Nakajima 1, 2, * , Kanika Sharma 1, * , June Young Lee 1 , Nicolas T. Maxim 1 , Mark A. Hicks 1 , Thien-Trang Vu 1 , Angela Luu 1 , W. Andrew Yeudall 3 , Nobuyuki Tanaka 2 , Hisashi Harada 1 1 Phillips Institute for Oral Health Research, School of Dentistry, Massey Cancer Center, Virginia Commonwealth University, Richmond, Virginia, USA 2 Department of Molecular Oncology, Institute for Advanced Medical Sciences, Nippon Medical School, Kawasaki, Japan 3 Department of Oral Biology, Dental College of Georgia, Augusta University, Augusta, Georgia, USA * These authors contributed equally to this work Correspondence to: Hisashi Harada, email: hharada@vcu.edu Keywords: CDK2, MCL-1, Noxa, phosphorylation, chemotherapy Received: September 08, 2015      Accepted: April 24, 2016      Published: May 07, 2016 ABSTRACT Noxa, a BH3-only pro-apoptotic BCL-2 family protein, causes apoptosis by specifically interacting with the anti-apoptotic protein MCL-1 to induce its proteasome-mediated degradation. We show here that the DNA damaging agents cisplatin and etoposide upregulate Noxa expression, which is required for the phosphorylation of MCL-1 at Ser64/Thr70 sites, proteasome-dependent degradation, and apoptosis. Noxa-induced MCL-1 phosphorylation at these sites occurs at the mitochondria and is primarily regulated by CDK2. MCL-1 and CDK2 form a stable complex and Noxa binds to this complex to facilitate the phosphorylation of MCL-1. When Ser64 and Thr70 of MCL-1 are substituted with alanine, the mutated MCL-1 is neither phosphorylated nor ubiquitinated, and becomes more stable than the wild-type protein. As a consequence, this mutant can inhibit apoptosis induced by Noxa overexpression or cisplatin treatment. These results indicate that Noxa-mediated MCL-1 phosphorylation followed by MCL-1 degradation is critical for apoptosis induced by DNA damaging agents through regulation of the Noxa/MCL-1/CDK2 complex." @default.
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• W2385011293 date "2016-05-07" @default.
• W2385011293 modified "2023-09-27" @default.
• W2385011293 title "DNA damaging agent-induced apoptosis is regulated by MCL-1 phosphorylation and degradation mediated by the Noxa/MCL-1/CDK2 complex" @default.
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• W2385011293 doi "https://doi.org/10.18632/oncotarget.9217" @default.
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