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A fibroblast protein binds the 3'-untranslated region of pro-alpha 1(I) collagen mRNA.

ABSTRACT: Post-transcriptional regulation of the expression of the pro alpha 1(I) chain of type I collagen (COL1A1) was studied by analysing cytoplasmic RNA-binding proteins and by transient transfections with collagen minigene plasmids. In this paper we present evidence for a factor from NIH 3T3 cells and human skin fibroblasts that interacts with the conserved 3'-untranslated region (UTR) of the shorter 4.8 kb mRNA species of the COL1A1 gene. The specificity of the interaction was confirmed by using (i) unlabelled specific and non-specific competitor RNAs and (ii) oligodeoxyribonucleotides annealed to the probe or used as single-stranded competitors. An antisense oligonucleotide annealed to the RNA probe near its 3'-terminus [20-42 nucleotides upstream of the first polyadenylation signal of the alpha 1(I) collagen mRNA] inhibited the binding, whereas other sense or antisense oligonucleotides had no effect on the interaction. The binding was sensitive to alkylation of free SH groups but not to phosphatase treatment of the extracts. In u.v. cross-linking analysis this factor migrated as a single polypeptide chain of about 67 kDa, and was named alpha 1-RBF67 (type I collagen alpha 1 chain RNA-binding factor). Dexamethasone treatment of fibroblasts, which is known to accelerate the turnover of COL1A1 mRNA, decreased the alpha 1-RBF67 activity markedly as evaluated by gel-retardation and u.v. cross-linking assays. Transient transfections with plasmids carrying the alpha 1(I) collagen promoter and 3'-UTR sequences demonstrated that the 3'-UTR participates in the response to dexamethasone. Thus the loss of alpha 1-RBF67 activity might be associated with decreased alpha 1(I) collagen mRNA levels after dexamethasone treatment.

SUBMITTER: Maatta A

PROVIDER: S-EPMC1134615 | biostudies-other | 1993 Nov

REPOSITORIES: biostudies-other

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Project description:Arterial stiffening, a characteristic feature of obesity and type 2 diabetes, contributes to the development and progression of cardiovascular diseases (CVD). Currently, no effective prophylaxis or therapeutics is available to prevent or treat arterial stiffening. A better understanding of the molecular mechanisms underlying arterial stiffening is vital to identify newer targets and strategies to reduce CVD burden. A major contributor to arterial stiffening is increased collagen deposition. In the 5'-untranslated regions of mRNAs encoding for type I collagen, an evolutionally conserved stem-loop (SL) structure plays an essential role in its stability and post-transcriptional regulation. Here, we show that feeding a high-fat/high-sucrose (HFHS) diet for 28 wk increases adiposity, insulin resistance, and blood pressure in male wild-type littermates. Moreover, arterial stiffness, assessed in vivo via aortic pulse wave velocity, and ex vivo using atomic force microscopy in aortic explants or pressure myography in isolated femoral and mesenteric arteries, was also increased in those mice. Notably, all these indices of arterial stiffness, along with collagen type I levels in the vasculature, were reduced in HFHS-fed mice harboring a mutation in the 5'SL structure, relative to wild-type littermates. This protective vascular phenotype in 5'SL-mutant mice did not associate with a reduction in insulin resistance or blood pressure. These findings implicate the 5'SL structure as a putative therapeutic target to prevent or reverse arterial stiffening and CVD associated with obesity and type 2 diabetes.NEW & NOTEWORTHY In the 5'-untranslated (UTR) regions of mRNAs encoding for type I collagen, an evolutionally conserved SL structure plays an essential role in its stability and posttranscriptional regulation. We demonstrate that a mutation of the SL mRNA structure in the 5'-UTR decreases collagen type I deposition and arterial stiffness in obese mice. Targeting this evolutionarily conserved SL structure may hold promise in the management of arterial stiffening and CVD associated with obesity and type 2 diabetes.

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A fibroblast protein binds the 3'-untranslated region of pro-alpha 1(I) collagen mRNA.

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