PMID- 16585196
OWN - NLM
STAT- MEDLINE
DCOM- 20060522
LR  - 20161128
IS  - 0008-5472 (Print)
IS  - 0008-5472 (Linking)
VI  - 66
IP  - 7
DP  - 2006 Apr 1
TI  - Inactivation of von Hippel-Lindau gene induces constitutive phosphorylation of 
      MET protein in clear cell renal carcinoma.
PG  - 3699-705
AB  - It is well known that inactivation of von Hippel-Lindau (VHL) gene predisposes 
      for human clear cell renal carcinoma (CCRC). However, details about critical 
      roles of VHL inactivation during tumorigenesis are still unknown. MET protein is 
      a tyrosine kinase receptor for hepatocyte growth factor/scatter factor (HGF/SF), 
      which regulates cell growth, cell morphology, and cell motility. We showed that 
      MET protein overexpressed in CCRC cells was phosphorylated without HGF/SF. This 
      constitutive phosphorylation of MET protein in CCRC cells was inhibited by the 
      rescue of exogenous wild-type VHL gene without a decrease in expression level of 
      MET protein. Interestingly, wild-type VHL gene suppressed the phosphorylation of 
      MET protein only under high cell density conditions. Additionally, MET protein 
      activated by the inactivation of VHL gene modified cell adherence, including 
      N-cadherin and beta-catenin. When activation of MET protein in CCRC cells was 
      inhibited by the MET inhibitor K252a, the growth of CCRC cells in vitro and the 
      tumorigenesis induced by CCRC cells in nude mice were suppressed. From these 
      results, we concluded that inactivation of VHL gene induced constitutive 
      phosphorylation of MET protein and modified intercellular adherence structure to 
      trigger the cell growth released from contact inhibition, finally resulting in 
      tumorigenesis. This is one of the mechanisms of CCRC oncogenesis, and MET protein 
      has potential as a molecular target for novel CCRC therapies.
FAU - Nakaigawa, Noboru
AU  - Nakaigawa N
AD  - Departments of Urology and Molecular Pathology, Yokohama City University Graduate 
      School of Medicine, 3-9 Fukuura Kanazawaku, Yokohama 236-0004, Japan. 
      nakaigan@med.yokohama-cu.ac.jp
FAU - Yao, Masahiro
AU  - Yao M
FAU - Baba, Masaya
AU  - Baba M
FAU - Kato, Shingo
AU  - Kato S
FAU - Kishida, Takeshi
AU  - Kishida T
FAU - Hattori, Keiko
AU  - Hattori K
FAU - Nagashima, Yoji
AU  - Nagashima Y
FAU - Kubota, Yoshinobu
AU  - Kubota Y
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Cancer Res
JT  - Cancer research
JID - 2984705R
RN  - 0 (Proto-Oncogene Proteins)
RN  - 0 (Receptors, Growth Factor)
RN  - EC 2.3.2.27 (Von Hippel-Lindau Tumor Suppressor Protein)
RN  - EC 2.7.10.1 (MET protein, human)
RN  - EC 2.7.10.1 (Proto-Oncogene Proteins c-met)
RN  - EC 6.3.2.- (VHL protein, human)
SB  - IM
MH  - Adenocarcinoma, Clear Cell/*genetics/metabolism
MH  - Carcinoma, Renal Cell/*genetics/metabolism
MH  - Cell Line, Tumor
MH  - Gene Expression Regulation, Neoplastic
MH  - Gene Silencing
MH  - Humans
MH  - Kidney Neoplasms/*genetics/metabolism
MH  - Phosphorylation
MH  - Proto-Oncogene Proteins/*metabolism
MH  - Proto-Oncogene Proteins c-met
MH  - Receptors, Growth Factor/*metabolism
MH  - Von Hippel-Lindau Tumor Suppressor Protein/*genetics
EDAT- 2006/04/06 09:00
MHDA- 2006/05/23 09:00
CRDT- 2006/04/06 09:00
PHST- 2006/04/06 09:00 [pubmed]
PHST- 2006/05/23 09:00 [medline]
PHST- 2006/04/06 09:00 [entrez]
AID - 66/7/3699 [pii]
AID - 10.1158/0008-5472.CAN-05-0617 [doi]
PST - ppublish
SO  - Cancer Res. 2006 Apr 1;66(7):3699-705. doi: 10.1158/0008-5472.CAN-05-0617.