H(2)O(2)-induced egr-1, fra-1, and c-jun gene expression is mediated by tyrosine kinase in aortic smooth muscle cells.
Hydrogen peroxide (H(2)O(2)) has recently been shown to have a dual effect on cell growth by stimulating proliferation and triggering apoptosis. Apoptosis induced by H(2)O(2) is a direct consequence of oxidant injury, while the proliferative response to H(2)O(2) is thought to be a protective mechanism against oxidant injury. Signaling of the H(2)O(2)-induced proliferative effect has been proposed to occur via the activation of mitogen-activated protein kinase (MAPK) and increase in expression of transcription factors. In the present study, H(2)O(2)-induced mitogenic signaling in aortic smooth muscle cells (ASMC) was investigated with a specific focus on the roles of tyrosine kinase and tyrosine phosphatase in the regulation of the H(2)O(2)-stimulated egr-1, fra-1, and c-jun transcription. The results show that H(2)O(2)-induced increases in egr-1, fra-1, and c-jun mRNA levels, as measured by Northern blot analysis, are time and dose dependent with the peak of the response within 2 h. Tyrosine kinase inhibitors (genistein, amino-genistein, and tyrphostin 51) significantly attenuated H(2)O(2)-induced expression of these genes and a tyrosine phosphatase inhibitor (perox-vanadate) stimulated their expression. H(2)O(2) stimulated tyrosine kinase activities and caused protein tyrosine phosphorylation, which was blocked by tyrphostin 51. H(2)O(2) also caused tyrosine phosphorylation of platelet derived growth factor (PDGF) receptor. These data show that H(2)O(2) increases egr-1, fra-1, and c-jun mRNA levels in vascular smooth muscle cells, and the increase in expression of these genes is mediated by activation of tyrosine kinase. Our data also provide evidence that the H(2)O(2)-induced mitogenic response is, in part, mediated through the receptor tyrosine kinase, PDGF receptor.
Jin
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N
Department of Physiology and Biophysics, Indiana University School of Medicine, Indianapolis, IN 46202, USA. njin@iupui.edu
Hatton
N D
ND
Harrington
M A
MA
Xia
X
X
Larsen
S H
SH
Rhoades
R A
RA
D000818:Animals; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000235:genetics; D051766:Early Growth Response Protein 1; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015870:Gene Expression / Q000187:drug effects*; D016758:Genes, jun / Q000187:drug effects; D019833:Genistein / Q000494:pharmacology; D006861:Hydrogen Peroxide / Q000633:toxicity*; D017874:Immediate-Early Proteins; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000378:metabolism*; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D016760:Proto-Oncogene Proteins c-fos / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017479:Receptors, Platelet-Derived Growth Factor / Q000737:chemistry / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics; D014443:Tyrosine / Q000737:chemistry / Q000378:metabolism; D020032:Tyrphostins / Q000494:pharmacology; D000099169:Fos-Related Antigen 1
D004268:DNA-Binding Proteins; D051766:Early Growth Response Protein 1; D004791:Enzyme Inhibitors; D019833:Genistein; D006861:Hydrogen Peroxide; D017874:Immediate-Early Proteins; D011505:Protein-Tyrosine Kinases; D016760:Proto-Oncogene Proteins c-fos; D012333:RNA, Messenger; D017479:Receptors, Platelet-Derived Growth Factor; D014157:Transcription Factors; D014443:Tyrosine; D020032:Tyrphostins; D000099169:Fos-Related Antigen 1; C486110:Egr1 protein, rat; C118515:tyrphostin 51