PMID- 10454537
OWN - NLM
STAT- MEDLINE
DCOM- 19990910
LR  - 20240314
IS  - 0270-7306 (Print)
IS  - 1098-5549 (Electronic)
IS  - 0270-7306 (Linking)
VI  - 19
IP  - 9
DP  - 1999 Sep
TI  - The von Hippel-Lindau tumor suppressor gene inhibits hepatocyte growth 
      factor/scatter factor-induced invasion and branching morphogenesis in renal 
      carcinoma cells.
PG  - 5902-12
AB  - Loss of function in the von Hippel-Lindau (VHL) tumor suppressor gene occurs in 
      familial and most sporadic renal cell carcinomas (RCCs). VHL has been linked to 
      the regulation of cell cycle cessation (G(0)) and to control of expression of 
      various mRNAs such as for vascular endothelial growth factor. RCC cells express 
      the Met receptor tyrosine kinase, and Met mediates invasion and branching 
      morphogenesis in many cell types in response to hepatocyte growth factor/scatter 
      factor (HGF/SF). We examined the HGF/SF responsiveness of RCC cells containing 
      endogenous mutated (mut) forms of the VHL protein (VHL-negative RCC) with that of 
      isogenic cells expressing exogenous wild-type (wt) VHL (VHL-positive RCC). We 
      found that VHL-negative 786-0 and UOK-101 RCC cells were highly invasive through 
      growth factor-reduced (GFR) Matrigel-coated filters and exhibited an extensive 
      branching morphogenesis phenotype in response to HGF/SF in the three-dimensional 
      (3D) GFR Matrigel cultures. In contrast, the phenotypes of A498 VHL-negative RCC 
      cells were weaker, and isogenic RCC cells ectopically expressing wt VHL did not 
      respond at all. We found that all VHL-negative RCC cells expressed reduced levels 
      of tissue inhibitor of metalloproteinase 2 (TIMP-2) relative to the wt 
      VHL-positive cells, implicating VHL in the regulation of this molecule. However, 
      consistent with the more invasive phenotype of the 786-0 and UOK-101 VHL-negative 
      RCC cells, the levels of TIMP-1 and TIMP-2 were reduced and levels of the matrix 
      metalloproteinases 2 and 9 were elevated compared to the noninvasive VHL-positive 
      RCC cells. Moreover, recombinant TIMPs completely blocked HGF/SF-mediated 
      branching morphogenesis, while neutralizing antibodies to the TIMPs stimulated 
      HGF/SF-mediated invasion in vitro. Thus, the loss of the VHL tumor suppressor 
      gene is central to changes that control tissue invasiveness, and a more invasive 
      phenotype requires additional genetic changes seen in some but not all RCC lines. 
      These studies also demonstrate a synergy between the loss of VHL function and Met 
      signaling.
FAU - Koochekpour, S
AU  - Koochekpour S
AD  - ABL Basic Research Program, NCI Frederick Cancer Research and Development Center, 
      Frederick, Maryland 21702, USA.
FAU - Jeffers, M
AU  - Jeffers M
FAU - Wang, P H
AU  - Wang PH
FAU - Gong, C
AU  - Gong C
FAU - Taylor, G A
AU  - Taylor GA
FAU - Roessler, L M
AU  - Roessler LM
FAU - Stearman, R
AU  - Stearman R
FAU - Vasselli, J R
AU  - Vasselli JR
FAU - Stetler-Stevenson, W G
AU  - Stetler-Stevenson WG
FAU - Kaelin, W G Jr
AU  - Kaelin WG Jr
FAU - Linehan, W M
AU  - Linehan WM
FAU - Klausner, R D
AU  - Klausner RD
FAU - Gnarra, J R
AU  - Gnarra JR
FAU - Vande Woude, G F
AU  - Vande Woude GF
LA  - eng
GR  - CA783356/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, P.H.S.
PL  - United States
TA  - Mol Cell Biol
JT  - Molecular and cellular biology
JID - 8109087
RN  - 0 (Proteins)
RN  - 0 (Tissue Inhibitor of Metalloproteinase-1)
RN  - 0 (Tumor Suppressor Proteins)
RN  - 127497-59-0 (Tissue Inhibitor of Metalloproteinase-2)
RN  - 67256-21-7 (Hepatocyte Growth Factor)
RN  - EC 2.3.2.27 (Ubiquitin-Protein Ligases)
RN  - EC 2.3.2.27 (Von Hippel-Lindau Tumor Suppressor Protein)
RN  - EC 2.7.10.1 (Receptor Protein-Tyrosine Kinases)
RN  - EC 3.4.- (Endopeptidases)
RN  - EC 6.- (Ligases)
RN  - EC 6.3.2.- (VHL protein, human)
SB  - IM
MH  - Carcinoma, Renal Cell/*genetics/pathology/physiopathology
MH  - Endopeptidases/metabolism
MH  - Extracellular Space/enzymology
MH  - Gene Expression
MH  - *Genes, Tumor Suppressor
MH  - Hepatocyte Growth Factor/antagonists & inhibitors/*pharmacology/physiology
MH  - Humans
MH  - Kidney Neoplasms/*genetics/pathology/physiopathology
MH  - *Ligases
MH  - Neoplasm Invasiveness
MH  - Phenotype
MH  - Proteins/*genetics
MH  - Receptor Protein-Tyrosine Kinases/metabolism
MH  - Tissue Inhibitor of Metalloproteinase-1/genetics/metabolism
MH  - Tissue Inhibitor of Metalloproteinase-2/genetics/metabolism
MH  - Tumor Cells, Cultured
MH  - *Tumor Suppressor Proteins
MH  - *Ubiquitin-Protein Ligases
MH  - Von Hippel-Lindau Tumor Suppressor Protein
MH  - von Hippel-Lindau Disease/*genetics
PMC - PMC84441
EDAT- 1999/08/24 10:00
MHDA- 2001/03/28 10:01
PMCR- 1999/09/01
CRDT- 1999/08/24 10:00
PHST- 1999/08/24 10:00 [pubmed]
PHST- 2001/03/28 10:01 [medline]
PHST- 1999/08/24 10:00 [entrez]
PHST- 1999/09/01 00:00 [pmc-release]
AID - 0362 [pii]
AID - 10.1128/MCB.19.9.5902 [doi]
PST - ppublish
SO  - Mol Cell Biol. 1999 Sep;19(9):5902-12. doi: 10.1128/MCB.19.9.5902.