期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 108, 期 47, 页码 18977-18982出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1103242108
关键词
necroptosis; chromosomal deficiency screen; tumor; scribble
资金
- Japanese Ministry of Education, Science, Sports, Culture, and Technology (MEXT)
- Japan Society for the Promotion of Science
- Keio Gijuku Academic Development Funds
- Keio University
- Strategic Research Foundation from MEXT
- Global Center of Excellence (G-COE) for Global Center for Education and Research in Integrative Membrane Biology
- International Human Frontier Science Program
- Japan Science and Technology Agency
- G-COE from MEXT
- Grants-in-Aid for Scientific Research [23650596, 21687019, 23122519, 19109003, 23229002, 23790236] Funding Source: KAKEN
Caspase-independent cell death is known to be important in physiological and pathological conditions, but its molecular regulation is not well-understood. Eiger is the sole fly ortholog of TNF. The ectopic expression of Eiger in the developing eye primordium caused JNK-dependent but caspase-independent cell death. To understand the molecular basis of this Eiger-induced nonapoptotic cell death, we performed a large-scale genetic screen in Drosophila for suppressors of the Eiger-induced cell death phenotype. We found that molecules that regulate metabolic energy production are central to this form of cell death: it was dramatically suppressed by decreased levels of molecules that regulate cytosolic glycolysis, mitochondrial beta-oxidation of fatty acids, the tricarboxylic acid cycle, and the electron transport chain. Importantly, reducing the expression of energy production-related genes did not affect the cell death triggered by proapoptotic genes, such as reaper, hid, or debcl, indicating that the energy production-related genes have a specific role in Eiger-induced nonapoptotic cell death. We also found that energy production-related genes regulate the Eiger-induced cell death downstream of JNK. In addition, Eiger induced the production of reactive oxygen species in a manner dependent on energy production-related genes. Furthermore, we showed that this cell death machinery is involved in Eiger's physiological function, because decreasing the energy production-related genes suppressed Eiger-dependent tumor suppression, an intrinsic mechanism for removing tumorigenic mutant clones from epithelia by inducing cell death. This result suggests a link between sensitivity to cell death and metabolic activity in cancer.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据