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Please use this identifier to cite or link to this item: http://hdl.handle.net/10564/3671

Title: The HNF-1β-USP28-Claspin pathway upregulates DNA damage-induced Chk1 activation in ovarian clear cell carcinoma.
Other Titles: 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
Authors: Ito, Fuminori
Yoshimoto, Chiharu
Yamada, Yuki
Sudo, Tamotsu
Kobayashi, Hiroshi
Keywords: hepatocyte nuclear factor-1β
DNA damage response
Issue Date: 3-Apr-2018
Publisher: Impact Journals
Citation: Oncotarget Vol.9 No.25 p.17512-17522 (2018 Apr)
Abstract: 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.
Description: 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 (CC BY 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 are credited.
URI: http://hdl.handle.net/10564/3671
ISSN: 19492553
Academic Degrees and number: 24601B1435
Degree-granting date: 2019-09-27
Degree name: 博士(医学)
Degree-granting institutions: 奈良県立医科大学
Appears in Collections:2019年度

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