TORC1 inactivation promotes APC/C-dependent mitotic slippage in yeast and human cells
Chihiro Yamada,
Aya Morooka,
Seira Miyazaki,
Masayoshi Nagai,
Satoru Mase,
Kenji Iemura,
Most Naoshia Tasnin,
Tsuneyuki Takuma,
Shotaro Nakamura,
Shamsul Morshed,
Naoki Koike,
Md. Golam Mostofa,
Muhammad Arifur Rahman,
Tasnuva Sharmin,
Haruko Katsuta,
Kotaro Ohara,
Kozo Tanaka,
Takashi Ushimaru
Affiliations
Chihiro Yamada
Department of Science, Graduate School of Integrated Science and Technology, Shizuoka University, Shizuoka 422-8021, Japan
Aya Morooka
Department of Biological Science, Faculty of Science, Shizuoka University, 836 Ohya, Suruga-ku, Shizuoka 422-8529, Japan
Seira Miyazaki
Department of Biological Science, Faculty of Science, Shizuoka University, 836 Ohya, Suruga-ku, Shizuoka 422-8529, Japan
Masayoshi Nagai
Department of Science, Graduate School of Integrated Science and Technology, Shizuoka University, Shizuoka 422-8021, Japan; Department of Molecular Oncology, Institute of Development, Aging and Cancer, Tohoku University, 4-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi 980-8575, Japan
Satoru Mase
Department of Science, Graduate School of Integrated Science and Technology, Shizuoka University, Shizuoka 422-8021, Japan
Kenji Iemura
Department of Molecular Oncology, Institute of Development, Aging and Cancer, Tohoku University, 4-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi 980-8575, Japan
Most Naoshia Tasnin
Graduate School of Science and Technology, Shizuoka University, Ohya 836, Suruga-ku, Shizuoka 422-8021, Japan
Tsuneyuki Takuma
Department of Science, Graduate School of Integrated Science and Technology, Shizuoka University, Shizuoka 422-8021, Japan
Shotaro Nakamura
Department of Science, Graduate School of Integrated Science and Technology, Shizuoka University, Shizuoka 422-8021, Japan
Shamsul Morshed
Graduate School of Science and Technology, Shizuoka University, Ohya 836, Suruga-ku, Shizuoka 422-8021, Japan
Naoki Koike
Graduate School of Science and Technology, Shizuoka University, Ohya 836, Suruga-ku, Shizuoka 422-8021, Japan
Md. Golam Mostofa
Graduate School of Science and Technology, Shizuoka University, Ohya 836, Suruga-ku, Shizuoka 422-8021, Japan
Muhammad Arifur Rahman
Graduate School of Science and Technology, Shizuoka University, Ohya 836, Suruga-ku, Shizuoka 422-8021, Japan
Tasnuva Sharmin
Graduate School of Science and Technology, Shizuoka University, Ohya 836, Suruga-ku, Shizuoka 422-8021, Japan
Haruko Katsuta
Department of Science, Graduate School of Integrated Science and Technology, Shizuoka University, Shizuoka 422-8021, Japan
Kotaro Ohara
Department of Biological Science, Faculty of Science, Shizuoka University, 836 Ohya, Suruga-ku, Shizuoka 422-8529, Japan
Kozo Tanaka
Department of Molecular Oncology, Institute of Development, Aging and Cancer, Tohoku University, 4-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi 980-8575, Japan
Takashi Ushimaru
Department of Science, Graduate School of Integrated Science and Technology, Shizuoka University, Shizuoka 422-8021, Japan; Department of Biological Science, Faculty of Science, Shizuoka University, 836 Ohya, Suruga-ku, Shizuoka 422-8529, Japan; Graduate School of Science and Technology, Shizuoka University, Ohya 836, Suruga-ku, Shizuoka 422-8021, Japan; Corresponding author
Summary: 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.
