Document Detail

VCP (p97) regulates NFkappaB signaling pathway, which is important for metastasis of osteosarcoma cell line.
MedLine Citation:
PMID:  11927012     Owner:  NLM     Status:  MEDLINE    
In order to identify genes associated with metastasis, suppression subtractive hybridization (SSH) was performed using murine osteosarcoma cell line Dunn and its subline with higher metastatic potential, LM8. SSH revealed expression of the gene encoding valosin-containing protein (VCP; also known as p97) to be constitutively activated in LM8 cells, but it declined in Dunn cells when the cells became confluent. Because VCP is known to be involved in the ubiquitination process of Inhibitor-kappaBalpha (IkappaBalpha), an inhibitor of nuclear factor-kappaB (NFkappaB), whether VCP influences NFkappaB activation or not was examined by using VCP-transfected Dunn cells (Dunn/VCPs). When stimulated with tumor necrosis factor-alpha (TNFalpha), Dunn/VCPs showed constantly activated NFkappaB, although in the original Dunn cells and control vector transfectant (Dunn/Dunn-c) NFkappaB activation ceased when the cells became confluent. Western immunoblot analysis showed an increase of phosphorylated IkappaBalpha (p-IkappaBalpha) in the cytoplasm of confluent Dunn/Dunn-c cells compared to that of Dunn/VCPs. Therefore, decrease of p-IkappaBalpha degrading activity might be responsible for the decrease in NFkappaB activation. In vitro apoptosis assay demonstrated increased apoptosis rates of Dunn/Dunn-c cells after TNFalpha stimulation compared to those of Dunn/VCPs and LM8 cells. In vivo metastasis assay showed increased incidences of metastatic events in Dunn/VCP-1 inoculated male C3H mice compared to those in Dunn/Dunn-c inoculated mice. These findings suggested that VCP expression plays an important role in the metastatic process. Anti-apoptotic potential in these cells owing to constant NFkappaB activation via efficient cytoplasmic p-IkappaBalpha degrading activity may explain the increased metastatic potential of these cells.
Tatsuya Asai; Yasuhiko Tomita; Shin-ichi Nakatsuka; Yoshihiko Hoshida; Akira Myoui; Hideki Yoshikawa; Katsuyuki Aozasa
Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Japanese journal of cancer research : Gann     Volume:  93     ISSN:  0910-5050     ISO Abbreviation:  Jpn. J. Cancer Res.     Publication Date:  2002 Mar 
Date Detail:
Created Date:  2002-04-02     Completed Date:  2002-06-20     Revised Date:  2009-09-03    
Medline Journal Info:
Nlm Unique ID:  8509412     Medline TA:  Jpn J Cancer Res     Country:  Japan    
Other Details:
Languages:  eng     Pagination:  296-304     Citation Subset:  IM    
Department of Pathology, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan.
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MeSH Terms
Adenosine Triphosphatases
Apoptosis / physiology
Blotting, Northern
Bone Neoplasms / metabolism*,  pathology
Cell Cycle Proteins / physiology*
DNA Primers / chemistry
Electrophoretic Mobility Shift Assay
Gene Expression Regulation
Lung Neoplasms / metabolism*,  secondary
Mice, Inbred C3H
Microscopy, Fluorescence
NF-kappa B / metabolism*
Osteosarcoma / metabolism*,  secondary
Reverse Transcriptase Polymerase Chain Reaction
Signal Transduction / genetics*
Tumor Cells, Cultured
Tumor Necrosis Factor-alpha / pharmacology,  physiology
Reg. No./Substance:
0/Cell Cycle Proteins; 0/DNA Primers; 0/NF-kappa B; 0/Tumor Necrosis Factor-alpha; EC 3.6.1.-/Adenosine Triphosphatases; EC 3.6.1.-/CDC48 protein

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