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

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.
Mesh Terms:
Animals, Antineoplastic Agents, Apoptosis, Cell Line, Tumor, Cells, Cultured, Cisplatin, Cyclin-Dependent Kinase 2, DNA Damage, Etoposide, HEK293 Cells, HeLa Cells, Humans, Immunoblotting, Mice, Mitochondria, Mutation, Myeloid Cell Leukemia Sequence 1 Protein, Phosphorylation, Proteolysis, Proto-Oncogene Proteins c-bcl-2, RNA Interference
Oncotarget
Date: Jun. 14, 2016
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