Depletion of p31comet protein promotes sensitivity to antimitotic drugs.

Abstract

Antimitotic spindle poisons are among the most important chemotherapeutic agents available. However, precocious mitotic exit by mitotic slippage limits the cytotoxicity of spindle poisons. The MAD2-binding protein p31(comet) is implicated in silencing the spindle assembly checkpoint after all kinetochores are attached to spindles. In this study, we report that the levels of p31(comet) and MAD2 in different cell lines are closely linked with susceptibility to mitotic slippage. Down-regulation of p31(comet) increased the sensitivity of multiple cancer cell lines to spindle poisons, including nocodazole, vincristine, and Taxol. In the absence of p31(comet), lower concentrations of spindle poisons were required to induce mitotic block. The delay in checkpoint silencing was induced by an accumulation of mitotic checkpoint complexes. The increase in the duration of mitotic block after p31(comet) depletion resulted in a dramatic increase in mitotic cell death upon challenge with spindle poisons. Significantly, cells that are normally prone to mitotic slippage and resistant to spindle disruption-mediated mitotic death were also sensitized after p31(comet) depletion. These results highlight the importance of p31(comet) in checkpoint silencing and its potential as a target for antimitotic therapies.

• Authors: Hoi Tang Ma, Yan Yan Chan, Xiao Chen, Kin Fan On, Randy Y C Poon
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 287 Issue 25 Pg. 21561-9 (Jun 15 2012) ISSN: 1083-351X [Electronic] United States
• PMID: 22544748 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Adaptor Proteins, Signal Transducing
• Antineoplastic Agents
• Cell Cycle Proteins
• Cytostatic Agents
• MAD2L1BP protein, human
• Nuclear Proteins

Topics

• Adaptor Proteins, Signal Transducing (genetics, metabolism)
• Antineoplastic Agents (pharmacology)
• Cell Cycle Proteins (genetics, metabolism)
• Cytostatic Agents (pharmacology)
• Drug Resistance, Neoplasm (drug effects, genetics)
• HeLa Cells
• Hep G2 Cells
• Humans
• Kinetochores (metabolism)
• Nuclear Proteins (genetics, metabolism)
• Spindle Apparatus (genetics, metabolism)