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p53 regulates nuclear GSK-3 levels through miR-34-mediated Axin2 suppression in colorectal cancer cells

Authors
 Nam Hee Kim  ;  Yong Hoon Cha  ;  Shi Eun Kang  ;  Yoonmi Lee  ;  Inhan Lee  ;  So Young Cha  ;  Joo Kyung Ryu  ;  Jung Min Na  ;  Changbum Park  ;  Ho-Geun Yoon  ;  Gyeong-Ju Park  ;  Jong In Yook  ;  Hyun Sil Kim 
Citation
 Cell Cycle, Vol.12(10) : 1578-1587, 2013 
Journal Title
 Cell Cycle 
ISSN
 1538-4101 
Issue Date
2013
Abstract
p53 is a bona fide tumor suppressor gene whose loss of function marks the most common genetic alteration in human malignancy. Although the causal link between loss of p53 function and tumorigenesis has been clearly demonstrated, the mechanistic links by which loss of p53 potentiates oncogenic signaling are not fully understood. Recent evidence indicates that the microRNA-34 (miR-34) family, a transcriptional target of the p53, directly suppresses a set of canonical Wnt genes and Snail, resulting in p53-mediated suppression of Wnt signaling and the EMT process. In this study, we report that p53 regulates GSK-3β nuclear localization via miR-34-mediated suppression of Axin2 in colorectal cancer. Exogenous miR-34a decreases Axin2 UTR-reporter activity through multiple binding sites within the 5′ and 3′ UTR of Axin2. Suppression of Axin2 by p53 or miR-34 increases nuclear GSK-3β abundance and leads to decreased Snail expression in colorectal cancer cells. Conversely, expression of the non-coding UTR of Axin2 causes depletion of endogenous miR-34 via the miR-sponge effect together with increased Axin2 function, supporting that the RNA-RNA interactions with Axin2 transcripts act as an endogenous decoy for miR-34. Further, RNA transcripts of miR-34 target were correlated with Axin2 in clinical data set of colorectal cancer patients. Although the biological relevance of nuclear GSK-3 level has not been fully studied, our results demonstrate that the tumor suppressor p53/miR-34 axis plays a role in regulating nuclear GSK-3 levels and Wnt signaling through the non-coding UTR of Axin2 in colorectal cancer.
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DOI
10.4161/cc.24739
Appears in Collections:
2. College of Dentistry (치과대학) > Dept. of Oral Pathology (구강병리학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Biochemistry and Molecular Biology (생화학-분자생물학교실) > 1. Journal Papers
5. Research Institutes (연구소) > Oral Cancer Research Institute (구강종양연구소) > 1. Journal Papers
Yonsei Authors
Kim, Nam Hee(김남희) ORCID logo https://orcid.org/0000-0002-3087-5276
Kim, Hyun Sil(김현실) ORCID logo https://orcid.org/0000-0003-3614-1764
Na, Jung Min(나정민)
Yook, Jong In(육종인) ORCID logo https://orcid.org/0000-0002-7318-6112
Yoon, Ho Geun(윤호근) ORCID logo https://orcid.org/0000-0003-2718-3372
Cha, So Young(차소영) ORCID logo https://orcid.org/0000-0002-2810-3883
Cha, Yong Hoon(차용훈) ORCID logo https://orcid.org/0000-0003-1761-3260
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URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/86967
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