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- Title
p31<sup>comet</sup>-Induced Cell Death Is Mediated by Binding and Inactivation of Mad2.
- Authors
Shin, Hyun-Jin; Park, Eun-Ran; Yun, Sun-Hee; Kim, Su-Hyeon; Jung, Won-Hee; Woo, Seon Rang; Joo, Hyun-Yoo; Jang, Su Hwa; Chung, Hee Yong; Hong, Sung Hee; Cho, Myung-Haing; Park, Joong-Jean; Yun, Miyong; Lee, Kee-Ho
- Abstract
Mad2, a key component of the spindle checkpoint, is closely associated with chromosomal instability and poor prognosis in cancer. p31comet is a Mad2-interacting protein that serves as a spindle checkpoint silencer at mitosis. In this study, we showed that p31comet-induced apoptosis and senescence occur via counteraction of Mad2 activity. Upon retroviral transduction of p31comet, the majority of human cancer cell lines tested lost the ability to form colonies in a low-density seeding assay. Cancer cells with p31comet overexpression underwent distinct apoptosis and/or senescence, irrespective of p53 status, confirming the cytotoxicity of p31comet. Interestingly, both cytotoxic and Mad2 binding activities were eliminated upon deletion of the C-terminal 30 amino acids of p31comet. Point mutation or deletion of the region affecting Mad2 binding additionally abolished cytotoxic activity. Consistently, wild-type Mad2 interacting with p31comet, but not its non-binding mutant, inhibited cell death, indicating that the mechanism of p31comet-induced cell death involves Mad2 inactivation. Our results clearly suggest that the regions of p31comet affecting interactions with Mad2, including the C-terminus, are essential for induction of cell death. The finding that p31comet-induced cell death is mediated by interactions with Mad2 that lead to its inactivation is potentially applicable in anticancer therapy.
- Subjects
CELL death; BINDING sites; CANCER prognosis; CELLULAR signal transduction; ANTINEOPLASTIC agents
- Publication
PLoS ONE, 2015, Vol 10, Issue 10, p1
- ISSN
1932-6203
- Publication type
Article
- DOI
10.1371/journal.pone.0141523