ABSTRACT
Elucidation of the regulation of type I collagen synthesis is critical for the understanding of pathophysiology of fibroproliferative disorders, wound healing, tissue remodeling and embryonic development. Transcriptional studies have shown that changes in collagen expression could not be explained solely by changes in the transcription rate of the collagen genes. Recently, it was discovered that stability of collagen α1(I) mRNA changes dramatically by culturing fibroblasts in matrix and by treatment with TGFβ, the most potent profibrotic cytokine. Evidence was provided that the signal transduction pathways leading to activation of phosphatidylinositol 3-kinase (PI3K) and ERK1/2 kinases are involved in this regulation. In hepatic stellate cells (HSCs), which are responsible for excessive collagen synthesis in liver fibrosis, stabilization of collagen α1(I) is primarily responsible for 50-70 fold increase in its steady state level. Two cis-acting sequences in collagen α1(I) mRNA have been identified which are responsible for this effect, 5` stem-loop and C-rich region in the 3` untranslated region (UTR). 5` stem-loop is involved in stabilization and translation of α1(I) mRNA in activated collagen producing, HSCs. This RNA element binds cytosolic and nuclear proteins in sequence specific manner. Sequestration of these proteins by a molecular decoy inhibited synthesis of type I a collagen by more than 50%. No binding to the 5` stem-loop was detected in collagen nonproducing quiescent HSCs, where collagen α1(I) mRNA has a short half-life. The 3` C-rich region binds α-CP, a known RNA binding protein involved in stabilization of several long-lived mRNAs. Binding of α-CP can be demonstrated only in extracts of activated HSCs. Differential binding of α-CP probably depends on phosphorylation status of the protein. Cloning of the 5` stem-loop binding proteins and elucidation of the posttranslational modifications of α-CP are critical for complete understanding of regulation of type I collagen synthesis.
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Branko Stefanovic, 2005. New Insights into Regulation of Type I Collagen Gene Expression. Journal of Biological Sciences, 5: 10-20.
DOI: 10.3923/jbs.2005.10.20
URL: https://scialert.net/abstract/?doi=jbs.2005.10.20
DOI: 10.3923/jbs.2005.10.20
URL: https://scialert.net/abstract/?doi=jbs.2005.10.20
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