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2 results on '"Ricupero DA"'

1. Phosphatidylinositol 3-kinase-dependent stabilization of alpha1(I) collagen mRNA in human lung fibroblasts.

Author

Ricupero DA, Poliks CF, Rishikof DC, Cuttle KA, Kuang PP, and Goldstein RH

Subjects
3T3 Cells, Androstadienes pharmacology, Animals, Blotting, Northern, Cells, Cultured, Chromones pharmacology, Collagen metabolism, Cycloheximide pharmacology, Dactinomycin pharmacology, Dose-Response Relationship, Drug, Enzyme Inhibitors pharmacology, Fibroblasts metabolism, Gene Expression Regulation, Humans, Immunoblotting, Kinetics, Lung cytology, Mice, Morpholines pharmacology, Nucleic Acid Synthesis Inhibitors pharmacology, Phosphoinositide-3 Kinase Inhibitors, Protein Synthesis Inhibitors pharmacology, Proto-Oncogene Proteins metabolism, Proto-Oncogene Proteins c-akt, RNA, Messenger genetics, Transfection, Wortmannin, Collagen genetics, Phosphatidylinositol 3-Kinases metabolism, Protein Serine-Threonine Kinases, RNA Stability genetics, RNA, Messenger metabolism
Abstract

We investigated the role of phosphatidylinositol 3-kinase (PI3K) in the expression of alpha1(I) collagen mRNA. We report that the basal level of alpha1(I) collagen mRNA was reduced when PI3K activity was inhibited by either LY-294002 or wortmannin. These PI3K inhibitors also blocked increases of alpha1(I) collagen mRNA levels after the addition of transforming growth factor-beta. The effect of PI3K inhibition was abolished by the removal of the inhibitor or by the addition of cycloheximide. Inhibition of PI3K activity decreased the stability of the alpha1(I) collagen mRNA with no change in the rate of transcription of the alpha1(I) collagen gene as assessed by Northern blotting with actinomycin D-treated fibroblasts and nuclear run-on assays. Expression of a truncated alpha1(I) collagen minigene driven by a cytomegalovirus promoter in murine fibroblasts was decreased by LY-294002 treatment. These data indicate that PI3K activation results in increased stabilization of alpha1(I) collagen mRNA. In vivo, the PI3K activity in fibroblasts may regulate basal levels of alpha1(I) collagen mRNA expression.

Published
2001
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2. Des-Arg(10)-kallidin engagement of the B1 receptor stimulates type I collagen synthesis via stabilization of connective tissue growth factor mRNA.

Author

Ricupero DA, Romero JR, Rishikof DC, and Goldstein RH

Subjects
Blotting, Northern, Calcium metabolism, Cell Line, Connective Tissue Growth Factor, Cycloheximide pharmacology, Cytosol metabolism, Fibroblasts metabolism, Growth Substances genetics, Humans, Immediate-Early Proteins genetics, Kallidin metabolism, Luciferases metabolism, Lung embryology, Protein Binding, Protein Synthesis Inhibitors pharmacology, RNA, Messenger metabolism, Receptor, Bradykinin B2, Tetradecanoylphorbol Acetate pharmacology, Time Factors, Transforming Growth Factor beta metabolism, Collagen biosynthesis, Growth Substances metabolism, Immediate-Early Proteins metabolism, Intercellular Signaling Peptides and Proteins, Kallidin analogs & derivatives, Receptors, Bradykinin metabolism
Abstract

Expression of the kinin B1 receptor is up-regulated in chronic inflammatory and fibrotic disorders; however, little is known about its role in fibrogenesis. We examined human embryonic lung fibroblasts that constitutively express the B1 receptor and report that engagement of the B1 receptor by des-Arg(10)-kallidin stabilized connective tissue growth factor (CTGF) mRNA, stimulated an increase in alpha1(I) collagen mRNA, and stimulated type I collagen production. These events were not observed in B2 receptor-activated fibroblasts. In addition, B1 receptor activation by des-Arg(10)-kallidin induced a rise in cytosolic Ca(2+) that is consistent with B1 receptor pharmacology. Our results show that the des-Arg(10)-kallidin-stimulated increase in alpha1(I) collagen mRNA was time- and dose-dependent, with a peak response observed at 20 h with 100 nM des-Arg(10)-kallidin. The increase in CTGF mRNA was also time- and dose-dependent, with a peak response observed at 4 h with 100 nM des-Arg(10)-kallidin. The increase in CTGF mRNA was blocked by the B1 receptor antagonist des-Arg(10),Leu(9)-kallidin. Inhibition of protein synthesis by cycloheximide did not block the des-Arg(10)-kallidin-induced increase in CTGF mRNA. These results suggest that engagement of the kinin B1 receptor contributes to fibrogenesis through increased expression of CTGF.

Published
2000
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