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Pellino 1 inactivates mitotic spindle checkpoint by targeting BubR1 for ubiquitinational degradation
Jihyun Park1, Hye-Young Park2, Suhyeon Kim3
1Department of Health Sciences and Technology, SAIHST, Sungkyunkwan University, Seoul 06351, Republic of Korea.
Abstract:
Aberrant constitutive activation of receptor-mediated downstream signalling plays an active role in the deregulation of cell cycle control. The mitotic spindle checkpoint is important in preventing abnormal mitotic cell cycle with chromosome missegregation from achieving neoplastic aneuploidy. However, mechanisms coupling receptor-mediated signalling to mitotic spindle checkpoint regulation remain unclear. Pellino 1 is a receptor signal-responsive E3 ubiquitin ligase, and the application of certain receptor-mediated signalling regulates the expression and activity of Pellino 1. In the present study, Pellino 1 expression induced extensive chromosome aneuploidy and allowed abnormal mitotic cells to adapt and become aneuploid in vitro and in vivo. Pellino 1 directly interacted with BubR1, a key component of mitotic spindle checkpoint, in a mitotic cell-cycle dependent manner, and down-regulated the stability of BubR1 by ubiquitination-mediated degradation and induced mitotic dysfunction. In summary, Pellino 1 expression acts as an inhibitory signal of the homeostatic regulation of mitotic cell cycle and checkpoint, and thus contributes to the initiation and progression of neoplastic chromosome aneuploidy.
Insights
Pellino 1, an E3 ubiquitin ligase, disrupts the cell cycle by targeting BubR1 for degradation. This leads to chromosome aneuploidy and mitotic dysfunction, contributing to cancer development.
Area of Science:
- Cell Biology
- Molecular Oncology
- Biochemistry
Background:
- Aberrant signaling pathways drive cell cycle deregulation and cancer.
- The mitotic spindle checkpoint prevents aneuploidy but its regulation by signaling pathways is unclear.
- Pellino 1 is an E3 ubiquitin ligase responsive to receptor-mediated signaling.
Purpose of the Study:
- To investigate the role of Pellino 1 in mitotic spindle checkpoint regulation.
- To elucidate the mechanisms by which Pellino 1 influences chromosome aneuploidy.
- To determine Pellino 1's contribution to neoplastic aneuploidy.
Main Methods:
- Assessed Pellino 1 expression in vitro and in vivo.
- Investigated Pellino 1 interaction with BubR1.
- Analyzed BubR1 stability and ubiquitination.
- Evaluated mitotic cell cycle progression and chromosome segregation.
Main Results:
- Pellino 1 expression induced significant chromosome aneuploidy.
- Pellino 1 directly interacted with BubR1 in a cell-cycle-dependent manner.
- Pellino 1 mediated BubR1 degradation via ubiquitination, causing mitotic dysfunction and aneuploidy.
Conclusions:
- Pellino 1 acts as an inhibitor of mitotic cell cycle and checkpoint homeostasis.
- Pellino 1 contributes to the initiation and progression of neoplastic aneuploidy.
- Targeting Pellino 1 may offer therapeutic strategies for aneuploidy-driven cancers.