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Ubiquitin ligase CHIP induces TRAF2 proteasomal degradation and NF-κB inactivation to regulate breast cancer cell invasion.

Authors
 Kang Won Jang  ;  Kyung Hye Lee  ;  Soo Hyuk Kim  ;  Taewon Jin  ;  Eun Young Choi  ;  Hyun Ju Jeon  ;  Eunsuk Kim  ;  Ye Sun Han  ;  Ji Hyung Chung 
Citation
 JOURNAL OF CELLULAR BIOCHEMISTRY, Vol.112(12) : 3612-3620, 2011 
Journal Title
JOURNAL OF CELLULAR BIOCHEMISTRY
ISSN
 0730-2312 
Issue Date
2011
MeSH
Base Sequence ; BreastNeoplasms/enzymology ; BreastNeoplasms/metabolism ; BreastNeoplasms/pathology* ; CellLine, Tumor ; DNA Primers ; Electrophoresis, Polyacrylamide Gel ; Female ; Humans ; NF-kappa B/metabolism* ; Neoplasm Invasiveness* ; Proteasome Endopeptidase Complex/metabolism* ; Proteolysis ; Real-Time Polymerase Chain Reaction ; TNF Receptor-Associated Factor 2/metabolism* ; Ubiquitin-Protein Ligases/metabolism*
Keywords
Chip ; Invasion ; NF‐kappaB ; TRAF2
Abstract
Transcriptional factor nuclear factor-kappaB (NF-κB) plays a crucial role in human breast cancer cell invasion and metastasis. The carboxyl terminus of Hsc70-interacting protein (CHIP) is a U-box-type ubiquitin ligase that induces ubiquitination and proteasomal degradation of its substrate proteins. In this study, we investigated the role of CHIP in the NF-κB pathway in the invasion of MDA-MB-231 cells, a highly aggressive breast cancer cell line. We showed that overexpression of CHIP significantly inhibits the invasion of the MDA-MB-231 cells. The overexpression of CHIP suppressed expression of urokinase plasminogen activator (uPA) and matrix metalloproteinase-9 (MMP-9) in MDA-MB-231 cells. Moreover, CHIP strongly inhibited the nuclear localization and the transcriptional activity of NF-κB. The activation of the IkappaB kinase complex (IKK) was also blocked by CHIP overexpression. Importantly, CHIP overexpression resulted in a significant decrease in the level of TNF receptor-associated factor 2 (TRAF2), an upstream key player in the NF-κB pathway. However, the level of TRAF2 was restored after treatment with a proteasome inhibitor, MG-132. Moreover, CHIP overexpression promoted the ubiquitination of TRAF2. We also found cell invasion significantly decreased in cells transfected with TRAF2 small interfering RNA (siRNA). In contrast, when CHIP expression was suppressed by siRNA in poorly invasive MCF-7 cells, cell invasion significantly increased in conjunction with enhanced NF-κB activation and TRAF2 levels. Taken together, these results suggest that CHIP regulates NF-κB-mediated cell invasion via the down-regulation of TRAF2.
Full Text
http://onlinelibrary.wiley.com/doi/10.1002/jcb.23292/abstract
DOI
10.1002/jcb.23292
Appears in Collections:
1. College of Medicine (의과대학) > Research Institute (부설연구소) > 1. Journal Papers
1. College of Medicine (의과대학) > Yonsei Biomedical Research Center (연세의생명연구원) > 1. Journal Papers
Yonsei Authors
Kim, Soo Hyuk(김수혁)
Kim, Eun Suk(김은숙)
Jang, Kang Won(장강원)
Jeon, Hyun Ju(전현주)
Chung, Ji Hyung(정지형)
Jin, Tae Won(진태원)
Choi, Eun Young(최은영)
URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/94275
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