Alternative Title卵巣明細胞癌においてHNF-1β -USP28-Claspin pathwayはDNA損傷によるChk1活性化を促進する
Note (General)type:Thesis
Transcription factor hepatocyte nuclear factor 1-beta (HNF-1β) enhances checkpoint kinase 1 (Chk1) activation and promotes G2/M cell cycle progression in ovarian clear cell carcinoma (CCC) following exposure to diverse genotoxic agents including bleomycin. However, the underlying mechanism leading to checkpoint activation of HNF-1β still remains largely unknown. To clarify the effects of HNF-1β on cell cycle checkpoints, human CCC cell lines were transfected with siRNAs targeting HNF-1β, Claspin, USP28, or a control vector. Ubiquitination and stabilization of Claspin protein by HNF-1β was assessed by immunoprecipitation. Loss-of-function studies using RNAi-mediated gene silencing indicated that HNF-1β facilitated the Claspin expression after treatment with a genotoxic agent bleomycin, resulting in accumulation of phosphorylated Chk1 (p-Chk1) and promotion of survival in CCC cell lines. This study showed for the first time that USP28, a de-ubiquitinase crucial for Claspin expression, is one target gene of HNF-1β. Knockdown of endogenous USP28 suppressed the Claspin expression and p-Chk1 activation and cell viability. Our findings identify a novel pathway of the HNF-1β-USP28-Claspin-Chk1 axis in checkpoint signal amplification in response to DNA damage. Targeting this pathway may represent a putative, novel, anticancer strategy in ovarian CCC.
博士(医学)・乙第1435号・令和元年9月27日
Copyright © 2018 Impact Journals, LLC
Copyright © Ito et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License 3.0 (CCBY 3.0 https://creativecommons.org/licenses/by/3.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source arecredited.
identifier:Oncotarget Vol.9 No.25 p.17512-17522 (2018 Apr)
identifier:19492553
identifier:http://ginmu.naramed-u.ac.jp/dspace/handle/10564/3671
identifier:Oncotarget, 9(25): 17512-17522
DOIinfo:doi/10.18632/oncotarget.24776
Collection (particular)国立国会図書館デジタルコレクション > デジタル化資料 > 博士論文
Date Accepted (W3CDTF)2020-05-25T09:38:44+09:00
Data Provider (Database)国立国会図書館 : 国立国会図書館デジタルコレクション