期刊
ISCIENCE
卷 25, 期 2, 页码 -出版社
CELL PRESS
DOI: 10.1016/j.isci.2021.103675
关键词
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资金
- Japan Society for the Promotion of Science (JSPS) [19370082, 23570225, 18K06212, 20H05317, 21H02475, 15H04368]
- MEXT [16H01296]
- Institute for Fermentation, Osaka [G-2020-2-055]
- Takeda Science Foundation Grant
- Tohoku University (the Cooperative Research Project Program of Joint Usage/Research Center at the Institute of Development, Aging and Cancer) [H28-6, H29-26, H30-1, R1-6, R2-95, R3-1]
- Grants-in-Aid for Scientific Research [21H02475, 20H05317, 16H01296, 15H04368] Funding Source: KAKEN
This study reveals that the inactivation of TORC1 kinase triggers mitotic slippage in yeast and human cells, leading to chromosome instability. However, the mechanism of mitotic slippage differs between yeast and human cells. This unexpected involvement of TORC1 in mitosis highlights the potential undesirable side effects of TORC1 inhibitors as immunosuppressants and anti-tumor drugs.
Unsatisfied kinetochore-microtubule attachment activates the spindle assembly checkpoint to inhibit the metaphase-anaphase transition. However, some cells eventually override mitotic arrest by mitotic slippage. Here, we show that inactivation of TORC1 kinase elicits mitotic slippage in budding yeast and human cells. Yeast mitotic slippage was accompanied with aberrant aspects, such as degradation of the nucleolar protein Net1, release of phosphatase Cdc14, and anaphase -promoting complex/cyclosome (APC/C)-Cdh1-dependent degradation of securin and cyclin B in metaphase. This mitotic slippage caused chromosome instability. In human cells, mammalian TORC1 (mTORC1) inactivation also invoked mitotic slippage, indicating that TORC1 inactivation-induced mitotic slippage is conserved from yeast to mammalian cells. However, the invoked mitotic slippage in human cells was not dependent on APC/C-Cdh1. This study revealed an unexpected involvement of TORC1 in mitosis and provides information on undesirable side effects of the use of TORC1 inhibitors as immunosuppressants and anti-tumor drugs.
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