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Enigma negatively regulates p53 through MDM2 and promotes tumor cell survival in mice

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Author(s)
Cho-Rok JungJung Hwa LimYoonjung ChoiDae-Ghon KimKoo Jeong KangSeung-Moo NohDong-Soo Im
Keimyung Author(s)
Kang, Koo Jeong
Department
Dept. of Surgery (외과학)
Journal Title
Journal of Clinical Investigation
Issued Date
2010
Volume
120
Issue
12
Abstract
The human E3 ubiquitin ligase murine double minute 2 (MDM2) targets the tumor suppressor p53 for ubiquitination and degradation but also promotes its own ubiquitination and subsequent degradation. As the balance between MDM2 and p53 levels plays a crucial role in regulating cell proliferation and apoptosis, we sought to identify factors selectively inhibiting MDM2 self-ubiquitination. Here we have shown that the LIM domain protein Enigma directly interacts with MDM2 to form a ternary complex with p53 in vitro and in human hepatoma and colon carcinoma cell lines and mouse embryonic fibroblasts. We found that Enigma elicited p53 degradation by inhibiting MDM2 self-ubiquitination and increasing its ubiquitin ligase activity toward p53 in cells. Moreover, mitogenic stimuli such as serum, FGF, and HGF increased Enigma transcription via induction of serum response factor (SRF), leading to MDM2 stabilization and subsequent p53 degradation. We observed similar results in the livers of mice treated with HGF. In humans, we found SRF and Enigma coexpressed with MDM2 but not p53 in several liver and stomach tumors. Finally, we showed that Enigma promoted cell survival and chemoresistance by suppressing p53-mediated apoptosis in both cell lines and a mouse xenograft model. Our findings suggest a role for Enigma in tumorigenesis and uncover a mechanism whereby mitogens attenuate p53 antiproliferative activity through an SRF/Enigma/MDM2 pathway.
Keimyung Author(s)(Kor)
강구정
Publisher
School of Medicine
Citation
Cho-Rok Jung et al. (2010). Enigma negatively regulates p53 through MDM2 and promotes tumor cell survival in mice. Journal of Clinical Investigation, 120(12), 4493–4506. doi: 10.1172/JCI42674
Type
Article
ISSN
0021-9738
DOI
10.1172/JCI42674
URI
https://kumel.medlib.dsmc.or.kr/handle/2015.oak/33981
Appears in Collections:
1. School of Medicine (의과대학) > Dept. of Surgery (외과학)
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