Abstract
The steady state levels of alpha1(I) collagen mRNA are decreased by retinoic acid and prostaglandin E2. These effector substances decrease the uptake of A system amino acids. We examined the effect of amino acid deprivation on the steady state levels of alpha1(I) collagen in human lung fibroblasts. Maintenance of fibroblasts in amino acid-free medium decreased alpha1(I) collagen mRNA levels by 29% at 24 h and 78% at 72 h. Frequent refeeding of cultures with amino acid-free medium resulted in more rapid decreases in intracellular amino acids and in alpha1(I) collagen mRNA levels. The decrease in alpha1(I) collagen mRNA levels was mediated by decreases in mRNA stability as assessed by a half-life determination using actinomycin D and by decreases in the rate of transcription as assessed by nuclear run-on assay. Treatment of fibroblasts with medium containing amino acids resulted in rapid restoration of alpha1(I) collagen mRNA levels. This increase in alpha1(I) collagen mRNA expression required protein synthesis as determined by cycloheximide sensitivity and was inhibited by prostaglandin E2. These data indicate that alpha1(I) collagen mRNA levels are sensitive to alterations in the amount of intracellular amino acids and suggest a potential mechanism whereby alpha1(I) collagen accumulation may be regulated independent of inflammatory mediators following lung injury.
Highlights
PGE2 and retinoic acid decrease the uptake of neutral amino acids transported by A system amino acids in lung fibroblasts [7, 8]
We examined the relation between amino acid depletion and ␣1(I) collagen mRNA levels in human lung fibroblasts
We find that amino acid depletion caused marked decreases in ␣1(I) collagen mRNA levels that rapidly reaccumulate following the addition of amino acids
Summary
PGE2 and retinoic acid decrease the uptake of neutral amino acids transported by A system amino acids in lung fibroblasts [7, 8]. The decreases in the steady state levels of ␣1(I) collagen mRNA occurred between 8 and 12 h following exposure This kinetic relation whereby decreases in amino acid uptake preceded decreases in collagen mRNA levels suggests that depletion of amino acid levels are associated with decreases in ␣1(I) mRNA levels. Asparagine synthetase mRNA is up-regulated by amino acid starvation, whereas -actin and glyceraldehyde 3-phosphate are decreased in abundance [11,12,13]. In these studies, we examined the relation between amino acid depletion and ␣1(I) collagen mRNA levels in human lung fibroblasts. We find that amino acid depletion caused marked decreases in ␣1(I) collagen mRNA levels that rapidly reaccumulate following the addition of amino acids. This decrease in ␣1(I) collagen mRNA was mediated by decreasing the rate of transcription of the ␣1(I) collagen gene and by decreasing the stability of the mRNA
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