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, William Andrew Yeudall, Nobuyuki Tanaka, Hisashi Harada

Research output: Contribution to journalArticle

12 Citations (Scopus)

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

Noxae
Phosphorylation
Apoptosis
DNA
Cisplatin
Apoptosis Regulatory Proteins
Etoposide
Proteasome Endopeptidase Complex
Alanine
Mitochondria
Proteins
Up-Regulation

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., ... 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

DNA damaging agent-induced apoptosis is regulated by MCL-1 phosphorylation and degradation mediated by the Noxa/MCL-1/CDK2 complex. / Nakajima, Wataru; Sharma, Kanika; Lee, June Young; Maxim, Nicolas T.; Hicks, Mark A.; Vu, Thien Trang; Luu, Angela; Yeudall, William Andrew; Tanaka, Nobuyuki; Harada, Hisashi.

In: Oncotarget, Vol. 7, No. 24, 01.01.2016, p. 36353-36365.

Research output: Contribution to journalArticle

Nakajima, W, Sharma, K, Lee, JY, Maxim, NT, Hicks, MA, Vu, TT, Luu, A, Yeudall, WA, 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, vol. 7, no. 24, pp. 36353-36365. https://doi.org/10.18632/oncotarget.9217
Nakajima, Wataru ; Sharma, Kanika ; Lee, June Young ; Maxim, Nicolas T. ; Hicks, Mark A. ; Vu, Thien Trang ; Luu, Angela ; Yeudall, William Andrew ; Tanaka, Nobuyuki ; Harada, Hisashi. / DNA damaging agent-induced apoptosis is regulated by MCL-1 phosphorylation and degradation mediated by the Noxa/MCL-1/CDK2 complex. In: Oncotarget. 2016 ; Vol. 7, No. 24. pp. 36353-36365.
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