2003 Fiscal Year Final Research Report Summary
Identification of the endoplasmic reticulum stress-specific caspase and its regulators in human
| Project/Area Number |
14599014
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
細胞死(アポトーシス)
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| Research Institution | RIKEN (The Institute of Physical and Chemical Research) |
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Principal Investigator |
MORISHIMA Nobuhiro RIKEN (The Institute of Physical and Chemical Research), Cellular and Molecular Biology Laboratory, Senior Scientist, 遺伝生化学研究室, 先任研究員 (40182232)
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| Project Period (FY) |
2002 – 2003
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| Keywords | apoptosis / caspase-12 / endoplasmic reticulum stress / ER stress / MAGE-3 / tumor antigen |
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| Research Abstract |
The caspase protease family plays a central role in 'the implementation of apoptosis in vertebrates. Caspases are constitutively expressed in healthy cells, where they are synthesized as precursor proteins (procaspases). Caspases are activated upon processing of procaspases. Therefore, the regulatory mechanism that controls caspase activation is significant for regulation of apoptosis.
Cell biological studies have already revealed that activation of caspase-12 from procaspase-12 is specifically induced by insult to the endoplasmic reticulum (ER), yet the regulatory mechanism of caspase-12 activation have been unclear. ER stress has received growing attention because it is considered a cause of pathologically relevant apoptosis. We have isolated by yeast two-hybrid screening from a HeLa cell cDNA library a human cancer antigen, MAGE-3,as a protein that specifically binds the procaspase-12. MAGE-3 is a member of the MAGE (melanoma associated antigen) gene family and is expressed in variou
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s types of tumor but not in normal tissues except for the testis. Consistent with the binding of MAGE-3 to procaspase-12, MAGE-3 protects procaspase-12 from processing by specifically binding the precursor. To examine the effect of MAGE-3 on caspase-12 activation in cells, we established stable transfectants that overexpress MAGE-3. Western blot analyses showed that stable expression of MAGE-3 rendered procaspase-12 insensitive to ER stress, thereby suppressing apoptosis. Although the parental cells underwent apoptosis in response to ER stress inducers, the stable transfectants were resistant to the inducers, undergoing apoptosis at the same low background level observed in untreated cells.
Although it remains unclear whether MAGE-3 plays any role in caspase regulation in tumor cells, our preliminary data show that endogenous MAGE-3 is detected in the microsomal fraction in several tumor cell lines (e.g., Jurkat) so far examined. Our results also show that overexpression of antisense MAGE-3 rendered Jurkat cells less resistant to ER stress, whereas the sense construct did not affect the resistance. These results support the theory that specific expression of MAGE-3 in tumor cells may be involved in resistance of tumor cells to ER stress. A study of the specific interactions between MAGE-3 and procaspase-12 may provide a basis for the development of therapeutic reagents against unwanted activation of caspases caused by ER stress. Less
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Research Products
(8 results)
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[Publications] Kasper, M., Seidel, D., Knels, L., Morishima, N., NeiBer, A., Bramke, S., Kosolowski, R.: "Early signs of lung fibrosis after in vitro treatment of rat lung slices with CdCl_2 and TGF-beta_1."Histochem. Cell Biol.. 121. 131-140 (2004)
Description
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