| Co-Investigator(Kenkyū-buntansha) |
ARAKI Yasuhiro The University of Tokyo, Graduate School of Pharmaceutical Sciences, Research Associate, 大学院・薬学系研究科, 助手 (60345254)
NISHINA Hiroshi The University of Tokyo, Graduate School of Pharmaceutical Sciences, Associate Professor, 大学院・薬学系研究科, 助教授 (60212122)
KATADA Toshiaki The University of Tokyo, Graduate School of Pharmaceutical Sciences, Professor, 大学院・薬学系研究科, 教授 (10088859)
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| Budget Amount *help |
¥4,100,000 (Direct Cost: ¥4,100,000)
Fiscal Year 2003: ¥1,800,000 (Direct Cost: ¥1,800,000)
Fiscal Year 2002: ¥2,300,000 (Direct Cost: ¥2,300,000)
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| Research Abstract |
The last step of gene expression is translation termination, in which synthesized polypeptide chain is released from the ribosome. So far, the termination is thought to occur only for terminating the translation reaction. During the course of investigation of the translation termination factor eRF3/GSPT, we have found that the translation termination is coupled to two post-termination events. One is mRNA decay and the other is translation initiation; the terminating ribosome is efficiently recycled to the next round of translation initiation in a manner coupled to translation termination, while at the same time, the translated mRNA is subjected to degradation. Therefore, transition termination is strongly suggested to be a regulatory step in gene expression. In the present study, we analyzed the detailed molecular mechanism of the termination-coupled mRNA decay. Translation termination is coupled to the shortening of poly(A) tail of mRNA, which is a first late limiting step of mRNA decay. One of the two major mRNA deadenylase, PAN, is involved in the termination coupled poly(A) shortening. As in the case with the yease Saccharomyces cerevisiae, human PAN, we have identified in this study, is involved in the deadenylation of mRNA. hPAN competes with eRF3/GSPT for binding to PABP, a poly(A)-binding protein which binds to the 3' poly(A) tail of mRNA, and the translation termination factor is replaced by hPAN as the translation progresses. Thus, hPAN is activated by PABP to degrade the poly(A) tail of the mRNA in a manner coupled to translation termination.
On the other hand, we have also found that eRF3/GSPT is involved in the regulation of apoptosis. eRF3/GSPT is cleaved at the PABP-binding site, and the processed eRF3/GSPT binds to an apoptosis inhibitor IAP to release activated caspases, leading to apoptosis. Also, translation termination might be a target of translation inhibition during apoptosis.
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