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Noxa determines localization and stability of MCL-1 and consequently ABT-737 sensitivity in small cell lung cancer
Bibliographic Information
- Published
- 2014-02-13
- Resource Type
- journal article
- Rights Information
-
- http://www.springer.com/tdm
- DOI
-
- 10.1038/cddis.2014.6
- Publisher
- Springer Science and Business Media LLC
Description
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.
Journal
-
- Cell Death & Disease
-
Cell Death & Disease 5 (2), e1052-e1052, 2014-02-13
Springer Science and Business Media LLC
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Keywords
- Proteasome Endopeptidase Complex
- Lung Neoplasms
- Cell Survival
- Antineoplastic Agents
- Apoptosis
- Transfection
- Piperazines
- Nitrophenols
- Animals
- Humans
- Phosphorylation
- Mice, Knockout
- Sulfonamides
- Dose-Response Relationship, Drug
- Protein Stability
- Biphenyl Compounds
- Ubiquitination
- Small Cell Lung Carcinoma
- Mitochondria
- Protein Transport
- HEK293 Cells
- Proto-Oncogene Proteins c-bcl-2
- Mutation
- Myeloid Cell Leukemia Sequence 1 Protein
- Original Article
- RNA Interference
- HeLa Cells
Details 詳細情報について
-
- CRID
- 1360567183352175872
-
- ISSN
- 20414889
-
- PubMed
- 24525728
-
- Article Type
- journal article
-
- Data Source
-
- Crossref
- KAKEN
- OpenAIRE
