1: Exp Cell Res. 2003 Nov 1;290(2):391-401. 

Hepatocyte growth factor signaling regulates transactivation of genes belonging
to the plasminogen activation system via hypoxia inducible factor-1.

Tacchini L, Matteucci E, De Ponti C, Desiderio MA.

Institute of General Pathology, University of Milano, via L. Mangiagalli, 31,
20133 Milano, Italy.

Hepatocyte growth factor (HGF) plays an important role in tumor growth and
progression also by regulating invasive/metastatic phenotype and angiogenesis.
Here we report that a molecular mechanism possibly contributing to these
functions of HGF may be hypoxia inducible factor-1 (HIF-1)-dependent expression
of genes of the plasminogen activation system. The following findings support
this conclusion: (1) HGF enhanced the activity of a luciferase reporter
construct under the control of multiple HIF-1 responsive elements (HRE) in HepG2
cells, and the cotransfection of the dominant negative for the beta-subunit
(ARNT) prevented this increase; (2) HGF activated uPA and PAI-1 promoters
through HIF-1 activity regulated by PI3K/JNK1 transducers, as demonstrated by
cotransfection with the reporter gene promoters and the dominant negative for
ARNT, p85 subunit of PI3K or JNK1; (3) hypoxia was additive to HGF in increasing
reporter vector activities, but probably through different transduction
pathways; (4) JNK1 wild-type expression vector increased HIF-1alpha protein
expression probably in a phosphorylated state and, thus, functional for
transactivating activity; and (5) c-Jun did not seem to be involved in the
activation of the luciferase construct containing multiple HREs because it was
not prevented by expression of TAM-67, which is the dominant negative mutant
form for c-Jun.

PMID: 14567996 [PubMed - indexed for MEDLINE]


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