title: Noxa determines localization and stability of MCL-1 and consequently ABT-737 sensitivity in small cell lung cancer.
abstract: The sensitivity to ABT-737, a prototype BH3 mimetic drug, varies in a broad range in small cell lung cancer (SCLC) cells. We have previously shown that the expression of Noxa, a BH3-only pro-apoptotic BCL-2 family protein, is the critical determinant of ABT-737 sensitivity. We show here that Noxa regulates the localization and stability of MCL-1, an anti-apoptotic member, which results in modulating ABT-737 sensitivity. Mutations in Noxa within the BH3 domain, the carboxyl terminus mitochondrial targeting domain, or of ubiquitinated lysines not only change the localization and stability of Noxa itself but also affect the mitochondrial localization and phosphorylation/ubiquitination status of MCL-1 and consequently modulate sensitivity to ABT-737. Results of studies utilizing these mutant proteins indicate that Noxa recruits MCL-1 from the cytosol to the mitochondria. Translocation of MCL-1 initiates its phosphorylation and subsequent ubiquitination, which triggers proteasome-mediated degradation. The precise regulatory mechanisms of Noxa/MCL-1 expression and stability could provide alternative targets to modulate apoptosis induced by BH3 mimetic drugs or other chemotherapeutic reagents.
authors: Department of Oral and Craniofacial Molecular Biology, School of Dentistry, Massey Cancer Center, Virginia Commonwealth University, Richmond, VA, USA.
authors: W
authors: W
authors: Nakajima
authors: Department of Oral and Craniofacial Molecular Biology, School of Dentistry, Massey Cancer Center, Virginia Commonwealth University, Richmond, VA, USA.
authors: M A
authors: MA
authors: Hicks
authors: Department of Molecular Oncology, Institute of Gerontology, Nippon Medical School, Kawasaki, Japan.
authors: N
authors: N
authors: Tanaka
authors: Department of Internal Medicine, Virginia Commonwealth University, McGuire Veterans Affairs Medical Center, Richmond, VA, USA.
authors: G W
authors: GW
authors: Krystal
authors: Department of Oral and Craniofacial Molecular Biology, School of Dentistry, Massey Cancer Center, Virginia Commonwealth University, Richmond, VA, USA.
authors: H
authors: H
authors: Harada
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001713:Biphenyl Compounds / Q000494:pharmacology*; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D018345:Mice, Knockout; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D009154:Mutation; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D009596:Nitrophenols / Q000494:pharmacology*; D010766:Phosphorylation; D010879:Piperazines / Q000494:pharmacology; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D055550:Protein Stability; D021381:Protein Transport; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D055752:Small Cell Lung Carcinoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D013449:Sulfonamides / Q000494:pharmacology*; D014162:Transfection; D054875:Ubiquitination
chemical_list: C501332:ABT-737; D000970:Antineoplastic Agents; D001713:Biphenyl Compounds; C579095:MCL1 protein, human; C579094:Mcl1 protein, mouse; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009596:Nitrophenols; C498702:PMAIP1 protein, human; D010879:Piperazines; D019253:Proto-Oncogene Proteins c-bcl-2; D013449:Sulfonamides; D046988:Proteasome Endopeptidase Complex