2011 Fiscal Year Final Research Report
Functhional analysis of tumor suppressur CHFR and development of novel daiagnotic and therapeutic strategies
| Project/Area Number |
22791293
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| Research Category |
Grant-in-Aid for Young Scientists (B)
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| Allocation Type | Single-year Grants |
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| Research Field |
Digestive surgery
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| Research Institution | Hokkaido University (2011)
Sapporo Medical University (2010) |
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Principal Investigator |
KASHIMA Lisa 北海道大学, 大学院・薬学研究院, 博士研究員 (30404750)
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| Project Period (FY) |
2010 – 2011
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| Keywords | 癌 / CHFR / PARP-1 / 細胞周期チェックポイント / ユビキチン化 / タキサン系抗癌剤 / PARP阻害剤 |
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| Research Abstract |
The mitotic checkpoint gene CHFR is silenced by promoter hypermethylation or mutated in various human cancers, suggesting that CHFR is an important tumor suppressor. Recent studies have reported that CHFR functions as an E3 ubiquitin ligase, resulting in the degradation of target proteins. To better understand how CHFR suppresses cell cycle progression and tumorigenesis, we sought to identify CHFR-interacting proteins using affinity purification combined with mass spectrometry. Herein, we showed poly(ADP-ribose) polymerase-1(PARP-1) to be a novel CHFR interacting protein. In CHFR expressing cells, mitotic stress induced the autoPARylation of PARP-1, resulting in an enhanced interaction between CHFR and PARP-1 and an increase in the polyubiquitination/degradation of PARP-1. The decrease in PARP-1 protein levels promoted cell cycle arrest at prophase, supporting that the cells expressing CHFR were resistant to microtubule inhibitors. By contrast, in CHFR-silenced cells, polyubiquitination was not induced in response to mitotic stress. Thus, PARP-1 protein levels did not decrease, and cells progressed into mitosis under mitotic stress, suggesting that CHFR-silenced cancer cells were sensitized to microtubule inhibitors. Furthermore, we found that cells from Chfr knockout mice and CHFRsilenced primary gastric cancer tissues expressed higher levels of PARP-1 protein, strongly supporting our data that the interaction between CHFR and PARP-1 plays an important role in cell cycle regulation and cancer therapeutic strategies. Based on our studies, we demonstrate a significant advantage for use of combinational chemotherapy with PARP inhibitors for cancer cells resistant to microtubule inhibitors.
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Research Products
(9 results)
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[Journal Article] CHFR Protein Regulates Mitotic Checkpoint by Targeting PARP-1 Protein for Ubiquitination and Degradation2012
Author(s)
Kashima L, Idogawa M, Mita H, Shitashige M, Yamada T, Ogi K, Suzuki H, Toyota M, Ariga H, Sasaki Y, Tokino T
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Journal Title
J Biol Chem
Volume: 287(16)
Pages: 12975-84
DOI
Peer Reviewed
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[Journal Article] Cysteine-rich intestinal protein 2(CRIP2) acts as a repressor of NF-{ kappa} B-mediated proangiogenic cytokine transcription to suppress tumorigenesis and angiogenesis2011
Author(s)
Cheung AK, Ko JM, Lung HL, Chan KW, Stanbridge EJ, Zabarovsky E, Tokino T, Kashima L, Suzuki T, Kwong DL, Chua D, Tsao SW, Lung ML
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Journal Title
PNAS
Volume: 108
Pages: 8390-95
DOI
Peer Reviewed
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