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

Research output: Contribution to journalArticle

15 Scopus citations

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 proteasomemediated 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.

Original languageEnglish (US)
Pages (from-to)36353-36365
Number of pages13
JournalOncotarget
Volume7
Issue number24
DOIs
StatePublished - Jan 1 2016

    Fingerprint

Keywords

  • CDK2
  • Chemotherapy
  • MCL-1
  • Noxa
  • Phosphorylation

ASJC Scopus subject areas

  • Oncology

Cite this

Nakajima, W., Sharma, K., Lee, J. Y., Maxim, N. T., Hicks, M. A., Vu, T. T., Luu, A., Yeudall, W. A., Tanaka, N., & Harada, H. (2016). DNA damaging agent-induced apoptosis is regulated by MCL-1 phosphorylation and degradation mediated by the Noxa/MCL-1/CDK2 complex. Oncotarget, 7(24), 36353-36365. https://doi.org/10.18632/oncotarget.9217