Oncotarget

Research Papers:

DNA damaging agent-induced apoptosis is regulated by MCL-1 phosphorylation and degradation mediated by the Noxa/MCL-1/CDK2 complex

Wataru Nakajima, Kanika Sharma, June Young Lee, Nicolas T. Maxim, Mark A. Hicks, Thien-Trang Vu, Angela Luu, W. Andrew Yeudall, Nobuyuki Tanaka, Hisashi Harada _

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Oncotarget. 2016; 7:36353-36365. https://doi.org/10.18632/oncotarget.9217

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Abstract

Wataru Nakajima1,2,*, Kanika Sharma1,*, June Young Lee1, Nicolas T. Maxim1, Mark A. Hicks1, Thien-Trang Vu1, Angela Luu1, W. Andrew Yeudall3, Nobuyuki Tanaka2, Hisashi Harada1

1Phillips Institute for Oral Health Research, School of Dentistry, Massey Cancer Center, Virginia Commonwealth University, Richmond, Virginia, USA

2Department of Molecular Oncology, Institute for Advanced Medical Sciences, Nippon Medical School, Kawasaki, Japan

3Department 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.


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