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Blood, 1 May 2001, Vol. 97, No. 9, pp. 2657-2666
HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY
The upstream stimulatory factor-2a inhibits plasminogen activator
inhibitor-1 gene expression by binding to a promoter element adjacent
to the hypoxia-inducible factor-1 binding site
Anatoly Samoylenko,
Ulrike Roth,
Kurt Jungermann, and
Thomas Kietzmann
From the Institut für Biochemie und Molekulare
Zellbiologie, Humboldtallee 23, Göttingen, Germany.
Plasminogen activator inhibitor-1 (PAI-1) expression is induced by
hypoxia (8% O2) via the PAI-1 promoter region  175/159 containing a hypoxia response element (HRE-2) binding the
hypoxia-inducible factor-1 (HIF-1) and an adjacent response element
(HRE-1) binding a so far unknown factor. The aim of the present study
was to identify this factor and to investigate its role in the
regulation of PAI-1 expression. It was found by supershift assays that
the upstream stimulatory factor-2a (USF-2a) bound mainly to the HRE-1
of the PAI-1 promoter and to a lesser extent to HRE-2. Overexpression of USF-2a inhibited PAI-1 messenger RNA and protein expression and
activated L-type pyruvate kinase expression in primary rat hepatocytes
under normoxia and hypoxia. Luciferase (Luc) gene constructs driven by
766 and 276 base pairs of the 5'-flanking region of the PAI-1 gene were
transfected into primary hepatocytes together with expression vectors
encoding wild-type USF-2a and a USF-2a mutant lacking DNA binding and
dimerization activity ( HU2a). Cotransfection of the wild-type USF-2a
vector reduced Luc activity by about 8-fold, whereas cotransfection of
HU2a did not influence Luc activity. Mutation of the HRE-1
(175/168) in the PAI-1 promoter Luc constructs decreased
USF-dependent inhibition of Luc activity. Mutation of the HRE-2
(165/158) was less effective. Cotransfection of a HIF-1 vector
could compete for the binding of USF at HRE-2. These results indicated
that the balance between 2 transcriptional factors, HIF-1 and USF-2a,
which can bind adjacent HRE sites, appears to be involved in the
regulation of PAI-1 expression in many clinical conditions.
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