The plasminogen activator inhibitor-1 gene is induced by cell adhesion through the MEK/ERK pathway.
The type-I plasminogen activator inhibitor (PAI-1), the primary inhibitor of both tissue-type and urokinase-type plasminogen activators (t-PA, u-PA), is the primary regulator of plasminogen activation and possibly of extracellular proteolysis. In anchorage-dependent cells, the PAI-1 gene is regulated by cell adhesion. PAI-1 gene expression is induced more evidently in cells that adhered to the culture plate than in those that did not adhere. In this study, we further demonstrate that the PAI-1 gene expression associated with cell adhesion is elicited through the activation of MEK and p42/p44 mitogen-activated protein (MAP) kinase (MAPK; ERK) signal pathways. We found that the MEK inhibitors, PD98059 and U0126, inhibited the induction of PAI-1 gene and protein expression during cell adhesion, PD98059 also inhibited the adhesion of cells to the culture plate, and cell adhesion elicited the kinase activities of MEK and ERK. In addition, we illustrate that two transcription response elements, the serum response element (SRE) and the hypoxia response element (HRE), which exist in the PAI-1 promoter, might be correlated with PAI-1 gene expression during cell adhesion. We discovered that the binding ability of nucleoproteins to both SRE and HRE was enhanced by cell adhesion and was dependent on MEK. Based on these results, we suggest that both MEK and ERK are involved in the induction of PAI-1 gene expression during cell adhesion. Furthermore, the subsequent downstream molecules, Elk-1 and HIF-1, may also participate.
Chang
Hang
H
Surgical Department, Shin Kong Wu Ho-Su Memorial Hospital, 95 Wen Chang Road, Shihlin, Taipei 111, Taiwan, ROC.
Shyu
Kou-Gi
KG
Lin
Shankung
S
Tsai
Shiow-Chwen
SC
Wang
Bao-Wei
BW
Liu
Ya-Chen
YC
Sung
Yu-Ling
YL
Lee
Chun-Chung
CC
D015153:Blotting, Western; D002070:Butadienes / Q000494:pharmacology; D002448:Cell Adhesion / Q000187:drug effects / Q000502:physiology; D017931:DNA Primers; D024202:Electrophoretic Mobility Shift Assay; D005419:Flavonoids / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D007124:Immunoenzyme Techniques; D020935:MAP Kinase Signaling System / Q000502:physiology*; D009570:Nitriles / Q000494:pharmacology; D017395:Plasminogen Activator Inhibitor 1 / Q000235:genetics* / Q000502:physiology*; D027602:Serum Response Element / Q000502:physiology; D014407:Tumor Cells, Cultured
D002070:Butadienes; D017931:DNA Primers; D005419:Flavonoids; D009570:Nitriles; D017395:Plasminogen Activator Inhibitor 1; C113580:U 0126; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one