Regulation of the hypoxia-dependent plasminogen activator inhibitor 1 expression by MAP kinases.
Mitogen-activated protein kinases (MAPKs) and protein kinase B (PKB) mediate growth and stress signals and have been implicated in the hypoxic response. Under hypoxic conditions, the expression of plasminogen activator inhibitor-1 (PAI-1) is mainly controlled by the hypoxia-inducible factor HIF-1. However, the role of MAPKs and PKB in HIF-1-mediated PAI-1 regulation is not clear. Treatment with the p38 inhibitor SB203580 and the PI3K inhibitor LY294002, but not with the MEK1 inhibitor PD98059, abrogated hypoxia-dependent PAI-1 induction in HepG2 cells. Consistently, overexpression of PKB or of the p38 upstream kinases MKK6 and MKK3 and of JNK, but not of ERK, enhanced PAI-1 mRNA levels. In MKK3-, MKK6- and PKB-expressing cells luciferase (Luc) activities from a hypoxia-inducible PAI-1-Luc construct or from a HIF-dependent Luc construct and, concomitantly, HIF-1alpha protein levels were enhanced. These findings indicate that p38- and PKB-dependent signalling pathways contribute to enhanced PAI-1 levels in the hypoxic response.
Kietzmann
Thomas
T
Institut für Biochemie und Molekulare Zellbiologie, Humboldtallee 23, D-37073 Göttingen, Germany. tkietzmn@gwdg.de
Jungermann
Kurt
K
Görlach
Agnes
A
D000818:Animals; D015152:Blotting, Northern; D015153:Blotting, Western; D002460:Cell Line; D003720:Densitometry; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005419:Flavonoids / Q000494:pharmacology; D005786:Gene Expression Regulation; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D000860:Hypoxia; D007093:Imidazoles / Q000494:pharmacology; D008156:Luciferases / Q000378:metabolism; D020935:MAP Kinase Signaling System; D008297:Male; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D010100:Oxygen / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D010957:Plasmids / Q000378:metabolism; D017395:Plasminogen Activator Inhibitor 1 / Q000096:biosynthesis*; D011401:Promoter Regions, Genetic; D011725:Pyridines / Q000494:pharmacology; D012313:RNA / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction; D013997:Time Factors; D015533:Transcriptional Activation; D014162:Transfection; D048051:p38 Mitogen-Activated Protein Kinases
D004791:Enzyme Inhibitors; D005419:Flavonoids; D007093:Imidazoles; D017395:Plasminogen Activator Inhibitor 1; D011725:Pyridines; D012333:RNA, Messenger; D012313:RNA; D008156:Luciferases; D019869:Phosphatidylinositol 3-Kinases; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; C093642:SB 203580; D010100:Oxygen; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one