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Sato, M. et al.

The PAI-1 gene as a direct target of endothelial PAS domain protein-1 in adenocarcinoma A549 cells.

Endothelial PAS domain protein-1 (EPAS1) regulates transcription of the genes encoding erythropoietin and vascular endothelial growth factor, which are important for maintaining oxygen homeostasis. We have previously shown that plasminogen activator inhibitor-1 (PAI-1) gene expression is induced by hypoxia. In this study, we sought to determine whether PAI-1 gene expression is directly regulated by EPAS1 in cancer cells because activities of proteases and their inhibitors are tightly regulated for tumor invasion. Hypoxia increased the PAI-1 mRNA levels in human adenocarcinoma A549 cells. Overexpression of EPAS1 significantly increased the PAI-1 mRNA and protein levels. Transient transfection assays revealed that EPAS1 increased PAI-1 gene transcription through a sequence containing 5'-CACGTACA-3' located at -194 (we refer to it as site HREPAI-1) and GT-box located at -78. Electrophoretic gel mobility shift assays revealed that HREPAI-1 serves as a binding site for EPAS1, and Sp1 constitutively binds to GT-box. In conclusion, PAI-1 expression is induced by EPAS1 through HREPAI-1 and through an Sp1-binding site. These results indicate that the PAI-1 gene is a direct target of EPAS1 and suggest the role of EPAS1 and Sp1 in the hypoxic response of cancer cells.[1]

References

The PAI-1 gene as a direct target of endothelial PAS domain protein-1 in adenocarcinoma A549 cells. Sato, M., Tanaka, T., Maemura, K., Uchiyama, T., Sato, H., Maeno, T., Suga, T., Iso, T., Ohyama, Y., Arai, M., Tamura, J., Sakamoto, H., Nagai, R., Kurabayashi, M. Am. J. Respir. Cell Mol. Biol. (2004) [Pubmed]

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