Cell type-dependent regulation of the hypoxia-responsive plasminogen activator inhibitor-1 gene by upstream stimulatory factor-2.
Transcriptional regulation of the plasminogen activator inhibitor type-1 (PAI-1) gene is an important issue since PAI-1 plays a crucial role in various pathological conditions. The transcription factor USF-2 was shown to be a negative regulator for rat PAI-1 expression, and therefore it was the aim of this study to evaluate the role of USF-2 for human PAI-1 expression. We found in human hepatoma cells (HepG2) that USF-2 induced human PAI-1 expression via two classical E-boxes and the hypoxia-responsive element (HRE) within the promoter. Gel-shift analyses showed that E-box 4 and E-box 5 bound USFs, and although the HRE contributed to the USF-dependent effects, it did not bind them. By contrast, USF-2 inhibited PAI-1 promoter activity in primary rat hepatocytes suggesting that PAI-1 expression depends on either the promoter context or USF activity which might be cell type-specific. Cotransfection of human or rat PAI-1 promoter luciferase constructs with expression vectors for wild-type USF-2 or USF-2 mutants in human HepG2 and rat H4IIE cells as well as in primary rat hepatocytes revealed that the effects of USF on PAI-1 expression depend on the cell type rather than the promoter context and that the USF-specific region domain of USF accounts for the observed cell type-specific effects.
Dimova
Elitsa Y
EY
Department of Biochemistry, Faculty of Chemistry, University of Kaiserslautern, D-67663 Kaiserslautern, Germany. edimova@gwdg.de
Kietzmann
Thomas
T
D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000473:pathology; D002478:Cells, Cultured; D006801:Humans; D000860:Hypoxia / Q000235:genetics*; D008099:Liver / Q000166:cytology; D008297:Male; D017395:Plasminogen Activator Inhibitor 1 / Q000235:genetics*; D011401:Promoter Regions, Genetic; D051381:Rats; D017208:Rats, Wistar; D051720:Upstream Stimulatory Factors / Q000502:physiology*
D017395:Plasminogen Activator Inhibitor 1; C497184:USF2 protein, human; D051720:Upstream Stimulatory Factors; C497187:Usf2 protein, rat