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 induct ion of heme oxygenase-1 (HO-1) mRNA in HeLa cells upon exposure to hem in, sodium arsenite and cadmium chloride was examined. The induction o f HO-1 mRNB by hemin was inhibited when the cells were pretreated with herbimycin A. Herbimycin also inhibited arsenite- and cadmium-depende nt induction of HO-1 mRNA in a dose-dependent manner, but less inhibit ion was observed in cadmium-treated cells than in ones treated with he min- or arsenite. Genistein (50 mu M), another tyrosine kinase inhibit or, also inhibited the induction of HO-1 mRNA by hemin, arsenite, and cadmium. Nuclear runoff assays revealed that herbimycin blocked the he min-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 molecula r mass of 66 kDa in the cells was increased by hemin- or arsenite-trea tment, and this increase was inhibited by treatment with 5 mu M herbim ycin. When HeLa cells were treated with a specific inhibitor of the mi togen-activated protein kinase (MAPK)/extracellular-signal regulated k inase cascade, PD58059 (100 mu M), suppression of the cadmium-dependen t HO-1 induction was not observed, but the hemin- or arsenite-dependen t induction was slightly inhibited. SB203580, an inhibitor of p38 MAPK , did not affect the HO-1 induction, These results indicated that sign al transduction involving tyrosine kinase rather than the MAPK family regulates the induction of human HO-1 gene expression by stress induce rs.