Noxa determines localization and stability of MCL-1 and consequently ABT-737 sensitivity in small cell lung cancer

Autor: Wataru Nakajima, Hisashi Harada, Mark A. Hicks, G W Krystal, Nobuyuki Tanaka
Rok vydání: 2013
Předmět:
Cancer Research
Lung Neoplasms
Apoptosis
Mitochondrion
Piperazines
Nitrophenols
0302 clinical medicine
Ubiquitin
RNA interference
hemic and lymphatic diseases
Phosphorylation
Mice
Knockout
0303 health sciences
Sulfonamides
Protein Stability
Transfection
Cell biology
Transport protein
Mitochondria
Biphenyl compound
Protein Transport
Proto-Oncogene Proteins c-bcl-2
030220 oncology & carcinogenesis
RNA Interference
Original Article
Proteasome Endopeptidase Complex
Cell Survival
Immunology
Antineoplastic Agents
Biology
03 medical and health sciences
Cellular and Molecular Neuroscience
Animals
Humans
030304 developmental biology
Dose-Response Relationship
Drug
ABT-737
Noxa
HEK 293 cells
Biphenyl Compounds
Ubiquitination
Cell Biology
Small Cell Lung Carcinoma
lung cancer
HEK293 Cells
Mutation
biology.protein
Myeloid Cell Leukemia Sequence 1 Protein
MCL-1
HeLa Cells
Zdroj: Cell Death & Disease
ISSN: 2041-4889
Popis: 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.
Databáze: OpenAIRE
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