title: DNA damaging agent-induced apoptosis is regulated by MCL-1 phosphorylation and degradation mediated by the Noxa/MCL-1/CDK2 complex.
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.
authors.affiliation: Phillips Institute for Oral Health Research, School of Dentistry, Massey Cancer Center, Virginia Commonwealth University, Richmond, Virginia, USA.|Department of Molecular Oncology, Institute for Advanced Medical Sciences, Nippon Medical School, Kawasaki, Japan.
authors.forename: Wataru
authors.initials: W
authors.lastname: Nakajima
authors.affiliation: Phillips Institute for Oral Health Research, School of Dentistry, Massey Cancer Center, Virginia Commonwealth University, Richmond, Virginia, USA.
authors.forename: Kanika
authors.initials: K
authors.lastname: Sharma
authors.affiliation: Phillips Institute for Oral Health Research, School of Dentistry, Massey Cancer Center, Virginia Commonwealth University, Richmond, Virginia, USA.
authors.forename: June Young
authors.initials: JY
authors.lastname: Lee
authors.affiliation: Phillips Institute for Oral Health Research, School of Dentistry, Massey Cancer Center, Virginia Commonwealth University, Richmond, Virginia, USA.
authors.forename: Nicolas T
authors.initials: NT
authors.lastname: Maxim
authors.affiliation: Phillips Institute for Oral Health Research, School of Dentistry, Massey Cancer Center, Virginia Commonwealth University, Richmond, Virginia, USA.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Hicks
authors.affiliation: Phillips Institute for Oral Health Research, School of Dentistry, Massey Cancer Center, Virginia Commonwealth University, Richmond, Virginia, USA.
authors.forename: Thien-Trang
authors.initials: TT
authors.lastname: Vu
authors.affiliation: Phillips Institute for Oral Health Research, School of Dentistry, Massey Cancer Center, Virginia Commonwealth University, Richmond, Virginia, USA.
authors.forename: Angela
authors.initials: A
authors.lastname: Luu
authors.affiliation: Department of Oral Biology, Dental College of Georgia, Augusta University, Augusta, Georgia, USA.
authors.forename: W Andrew
authors.initials: WA
authors.lastname: Yeudall
authors.affiliation: Department of Molecular Oncology, Institute for Advanced Medical Sciences, Nippon Medical School, Kawasaki, Japan.
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Tanaka
authors.affiliation: Phillips Institute for Oral Health Research, School of Dentistry, Massey Cancer Center, Virginia Commonwealth University, Richmond, Virginia, USA.
authors.forename: Hisashi
authors.initials: H
authors.lastname: Harada
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D002945:Cisplatin / Q000494:pharmacology; D051357:Cyclin-Dependent Kinase 2 / Q000235:genetics / Q000378:metabolism*; D004249:DNA Damage; D005047:Etoposide / Q000494:pharmacology; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D015151:Immunoblotting; D051379:Mice; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D009154:Mutation; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D059748:Proteolysis / Q000187:drug effects; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference
chemical_list: D000970:Antineoplastic Agents; C579095:MCL1 protein, human; D064549:Myeloid Cell Leukemia Sequence 1 Protein; C498702:PMAIP1 protein, human; D019253:Proto-Oncogene Proteins c-bcl-2; D005047:Etoposide; C495894:CDK2 protein, human; D051357:Cyclin-Dependent Kinase 2; D002945:Cisplatin
keywords: CDK2; MCL-1; Noxa; chemotherapy; phosphorylation