Evidence that an iron chelator regulates collagen synthesis by decreasing the stability of procollagen mRNA.
Iron chelation has been shown previously to decrease collagen synthesis at a posttranslational level by inhibiting prolyl 4-hydroxylase, one of the key enzymes in collagen metabolism. On the other hand, recent in vivo studies of iron overload in rats suggest that iron could specifically activate collagen gene expression in liver tissues. These findings led us to investigate whether iron chelation might also affect collagen gene expression and posttranslational modification. Our data indicate that alpha,alpha'-dipyridyl, an iron chelator, at a concentration of 1 mmol/L, decreased steady-state levels of type I procollagen messenger RNA by 42% (p less than 0.001) without affecting beta-actin messenger RNA levels. Nuclear runoff studies demonstrated that transcription of the type I procollagen gene was unchanged by alpha,alpha'-dipyridyl. However, the turnover rate of type I procollagen messenger RNA was increased by 30%. This pretranslational inhibition of collagen synthesis was not due to decreased lipid peroxidation, because thiobarbituric acid-reactive substances were unchanged by alpha,alpha'-dipyridyl. However, cycloheximide totally abolished the effect, indicating that de novo protein synthesis was required.
Ikeda
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Department of Medicine, University of Connecticut School of Medicine, Farmington 06030.
Wu
G Y
GY
Wu
C H
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D015082:2,2'-Dipyridyl / Q000494:pharmacology; D003094:Collagen / Q000096:biosynthesis*; D003513:Cycloheximide / Q000494:pharmacology; D004355:Drug Stability; D006706:Homeostasis; D006801:Humans; D007502:Iron Chelating Agents / Q000494:pharmacology*; D011347:Procollagen / Q000235:genetics*; D012333:RNA, Messenger / Q000378:metabolism*; D014158:Transcription, Genetic
D007502:Iron Chelating Agents; D011347:Procollagen; D012333:RNA, Messenger; D015082:2,2'-Dipyridyl; D003094:Collagen; D003513:Cycloheximide