PMID- 10347197
OWN - NLM
STAT- MEDLINE
DCOM- 19990701
LR  - 20210209
IS  - 0021-9258 (Print)
IS  - 0021-9258 (Linking)
VI  - 274
IP  - 23
DP  - 1999 Jun 4
TI  - Activation mechanisms of the urokinase-type plasminogen activator promoter by 
      hepatocyte growth factor/scatter factor.
PG  - 16377-86
AB  - Hepatocyte growth factor/scatter factor (HGF/SF) is a pleiotropic effector 
      inducing invasion and metastasis of tumor cells that express the Met tyrosine 
      kinase receptor. One of the effectors of HGF/SF is the urokinase-type plasminogen 
      activator, a serine protease that facilitates tumor progression and metastasis by 
      controlling the synthesis of the extracellular matrix degrading plasmin. 
      Stimulation of NIH 3T3 cells that were stably transfected with the human Met 
      receptor (NIH 3T3-Methum) with HGF/SF induced a trans-activation of the urokinase 
      promoter and urokinase secretion. Induction of the urokinase promoter by HGF/SF 
      via the Met receptor was blocked by co-expression of a dominant-negative Grb2 and 
      Sos1 expression construct. Further, the expression of the catalytically inactive 
      mutants of Ha-Ras, RhoA, c-Raf, and Erk2 or addition of the Mek1-specific 
      inhibitor PD 098059 abrogated the stimulation of the urokinase promoter by 
      HGF/SF. A sequence residing between -2109 and -1870 base pairs (bp) was critical 
      for stimulation of the urokinase gene by HGF/SF. Mobility shift assays with 
      oligonucleotides spanning an AP-1 site at -1880 bp or a combined PEA3/AP-1 site 
      at -1967 bp showed binding of nuclear factors from NIH 3T3-Methum cells. 
      Expression of an expression plasmid that inhibits DNA binding of AP-1 proteins 
      (A-Fos) abrogated inducible and basal activation of the urokinase promoter. 
      Nuclear extract from unstimulated NIH 3T3-Methum cells contained more JunD and 
      showed a stronger JunD supershift with the AP-1 oligonucleotides, compared with 
      HGF/SF-stimulated cells. Consistent with the levels of JunD expression being 
      functionally important for basal expression of the urokinase promoter, we found 
      that overexpression of wild type JunD inhibited the induction of the urokinase 
      promoter by HGF/SF. These data suggest that the induction of urokinase by HGF/SF 
      is regulated by a Grb2/Sos1/Ha-Ras/c-Raf/RhoA/Mek1/Erk2/c-++ +Jun-dependent 
      mitogen-activated protein kinase pathway.
FAU - Ried, S
AU  - Ried S
AD  - Department of Obstetrics and Gynecology, Technische Universitat Munchen, D-81675 
      Munchen, Germany.
FAU - Jager, C
AU  - Jager C
FAU - Jeffers, M
AU  - Jeffers M
FAU - Vande Woude, G F
AU  - Vande Woude GF
FAU - Graeff, H
AU  - Graeff H
FAU - Schmitt, M
AU  - Schmitt M
FAU - Lengyel, E
AU  - Lengyel E
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - J Biol Chem
JT  - The Journal of biological chemistry
JID - 2985121R
RN  - 0 (Protein Precursors)
RN  - 0 (Transcription Factor AP-1)
RN  - 0 (pro-hepatocyte growth factor)
RN  - 67256-21-7 (Hepatocyte Growth Factor)
RN  - 9007-49-2 (DNA)
RN  - EC 2.7.10.1 (Proto-Oncogene Proteins c-met)
RN  - EC 3.4.21.73 (Urokinase-Type Plasminogen Activator)
SB  - IM
MH  - 3T3 Cells
MH  - Animals
MH  - DNA/metabolism
MH  - Enzyme Activation
MH  - *Gene Expression Regulation, Enzymologic
MH  - Hepatocyte Growth Factor/*metabolism
MH  - Humans
MH  - Mice
MH  - *Promoter Regions, Genetic
MH  - Protein Precursors/*metabolism
MH  - Proto-Oncogene Proteins c-met/metabolism
MH  - Signal Transduction
MH  - Transcription Factor AP-1/metabolism
MH  - Up-Regulation
MH  - Urokinase-Type Plasminogen Activator/*genetics/metabolism
EDAT- 1999/05/29 00:00
MHDA- 1999/05/29 00:01
CRDT- 1999/05/29 00:00
PHST- 1999/05/29 00:00 [pubmed]
PHST- 1999/05/29 00:01 [medline]
PHST- 1999/05/29 00:00 [entrez]
AID - S0021-9258(19)72982-2 [pii]
AID - 10.1074/jbc.274.23.16377 [doi]
PST - ppublish
SO  - J Biol Chem. 1999 Jun 4;274(23):16377-86. doi: 10.1074/jbc.274.23.16377.