Involvement of the tyrosine phosphorylation pathway in induction of human heme oxygenase-1 by hemin, sodium arsenite, and cadmium chloride.
The effect of a tyrosine kinase inhibitor, herbimycin A, on the induction of heme oxygenase-1 (HO-1) mRNA in HeLa cells upon exposure to hemin, sodium arsenite and cadmium chloride was examined. The induction of HO-1 mRNA by hemin was inhibited when the cells were pretreated with herbimycin A. Herbimycin also inhibited arsenite- and cadmium-dependent induction of HO-1 mRNA in a dose-dependent manner, but less inhibition was observed in cadmium-treated cells than in ones treated with hemin- or arsenite. Genistein (50 microM), another tyrosine kinase inhibitor, also inhibited the induction of HO-1 mRNA by hemin, arsenite, and cadmium. Nuclear runoff assays revealed that herbimycin blocked the hemin-induced transcription of the HO-1 gene. The induction of HO-1 mRNA by hemin in human peripheral blood mononuclear cells was inhibited by herbimycin. The tyrosine phosphorylation of a protein with a molecular mass of 66 kDa in the cells was increased by hemin- or arsenite-treatment, and this increase was inhibited by treatment with 5 microM herbimycin. When HeLa cells were treated with a specific inhibitor of the mitogen-activated protein kinase (MAPK)/extracellular-signal regulated kinase cascade, PD58059 (100 microM), suppression of the cadmium-dependent HO-1 induction was not observed, but the hemin- or arsenite-dependent induction was slightly inhibited. SB203580, an inhibitor of p38 MAPK, did not affect the HO-1 induction. These results indicated that signal transduction involving tyrosine kinase rather than the MAPK family regulates the induction of human HO-1 gene expression by stress inducers.
Second Department of Surgery Kansai Medical University, Moriguchi, Osaka, 570-8506, Japan.
Y
Y
Masuya
K
K
Hioki
R
R
Tokunaga
S
S
Taketani
D018053:Arsenites / Q000494:pharmacology*; D016227:Benzoquinones; D019256:Cadmium Chloride / Q000494:pharmacology*; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000037:antagonists & inhibitors; D004790:Enzyme Induction; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006367:HeLa Cells; D006419:Heme Oxygenase (Decyclizing) / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D051547:Heme Oxygenase-1; D006427:Hemin / Q000494:pharmacology*; D006801:Humans; D047029:Lactams, Macrocyclic; D008565:Membrane Proteins; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D011809:Quinones / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics; D017828:Rifabutin / Q000031:analogs & derivatives; D017670:Sodium Compounds / Q000494:pharmacology*; D014158:Transcription, Genetic / Q000187:drug effects; D014443:Tyrosine / Q000378:metabolism*
D018053:Arsenites; D016227:Benzoquinones; D004791:Enzyme Inhibitors; D047029:Lactams, Macrocyclic; D008565:Membrane Proteins; D011809:Quinones; D012333:RNA, Messenger; D017670:Sodium Compounds; D017828:Rifabutin; D014443:Tyrosine; C017947:sodium arsenite; C020754:herbimycin; D006427:Hemin; C496541:HMOX1 protein, human; D006419:Heme Oxygenase (Decyclizing); D051547:Heme Oxygenase-1; D011505:Protein-Tyrosine Kinases; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D019256:Cadmium Chloride