Presser
03-03-2014, 10:59 AM
Insulin-Like Growth Factor-1 Increases Synthesis of Collagen Type I via Induction of the mRNA-Binding Protein LARP6 Expression and Binding to the 5' Stem-loop of Col1a1 and Col1a2 mRNA.
Blackstock C1, Higashi Y, Sukhanov S, Shai SY, Stefanovic B, Tabony AM, Yoshida T, Delafontaine P.
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AbstractCollagen content in atherosclerotic plaque is a hallmark of plaque stability. Our earlier studies showed that insulin-like growth factor-1 (IGF-1) increases collagen content in atherosclerotic plaques of Apoe-/- mice. To identify mechanisms we investigated the effect of IGF-1 on the la ribonucleoprotein domain family member 6 (LARP6). LARP6 binds a stem-loop motif in the 5'UTR of the mRNAs encoding the collagen type I alpha subunits (α1(I) and α2(I)), and coordinates their translation into the heterotrimeric collagen type I molecule. In human aortic smooth muscle cells (SMCs), IGF-1 rapidly increased LARP6 expression and the rate of collagen synthesis and extracellular accumulation. IGF-1 increased both LARP6 and collagen type I expression via a posttranscriptional and translation-dependent mechanism involving PI3K/Akt/p70S6k-signaling. Immunoprecipitation of LARP6, followed by qPCR indicated that IGF-1 increased the level of COL1a1 and COL1a2 mRNA bound to LARP6. Mutation of the 5'stem-loop of Col1a1 mRNA, which inhibits binding of LARP6, abolished the ability of IGF-1 to increase synthesis of collagen type I. Furthermore, overexpression of a 5'stem-loop RNA molecular decoy that sequesters LARP6, prevented the ability of IGF-1 to increase pro-α1(I) and mature α1(I) expression in cultured medium. IGF-1 infusion in Apoe-/- mice increased expression of LARP6 and pro-α1(I) in aortic lysates, and SMC-specific IGF-1-overexpression robustly increased collagen fibrillogenesis in atherosclerotic plaque. In conclusion, we identify LARP6 as a critical mediator by which IGF-1 augments synthesis of collagen type I in vascular smooth muscle, which may play an important role in promoting atherosclerotic plaque stability.
KEYWORDS:5'Stem-loop, Acheron, Akt, Atherosclerosis, Fibrillogenesis, Insulin-like growth factor (IGF), Protein synthesis, Translation, Vascular smoothmuscle cells, posttranscriptional
Blackstock C1, Higashi Y, Sukhanov S, Shai SY, Stefanovic B, Tabony AM, Yoshida T, Delafontaine P.
Author information
AbstractCollagen content in atherosclerotic plaque is a hallmark of plaque stability. Our earlier studies showed that insulin-like growth factor-1 (IGF-1) increases collagen content in atherosclerotic plaques of Apoe-/- mice. To identify mechanisms we investigated the effect of IGF-1 on the la ribonucleoprotein domain family member 6 (LARP6). LARP6 binds a stem-loop motif in the 5'UTR of the mRNAs encoding the collagen type I alpha subunits (α1(I) and α2(I)), and coordinates their translation into the heterotrimeric collagen type I molecule. In human aortic smooth muscle cells (SMCs), IGF-1 rapidly increased LARP6 expression and the rate of collagen synthesis and extracellular accumulation. IGF-1 increased both LARP6 and collagen type I expression via a posttranscriptional and translation-dependent mechanism involving PI3K/Akt/p70S6k-signaling. Immunoprecipitation of LARP6, followed by qPCR indicated that IGF-1 increased the level of COL1a1 and COL1a2 mRNA bound to LARP6. Mutation of the 5'stem-loop of Col1a1 mRNA, which inhibits binding of LARP6, abolished the ability of IGF-1 to increase synthesis of collagen type I. Furthermore, overexpression of a 5'stem-loop RNA molecular decoy that sequesters LARP6, prevented the ability of IGF-1 to increase pro-α1(I) and mature α1(I) expression in cultured medium. IGF-1 infusion in Apoe-/- mice increased expression of LARP6 and pro-α1(I) in aortic lysates, and SMC-specific IGF-1-overexpression robustly increased collagen fibrillogenesis in atherosclerotic plaque. In conclusion, we identify LARP6 as a critical mediator by which IGF-1 augments synthesis of collagen type I in vascular smooth muscle, which may play an important role in promoting atherosclerotic plaque stability.
KEYWORDS:5'Stem-loop, Acheron, Akt, Atherosclerosis, Fibrillogenesis, Insulin-like growth factor (IGF), Protein synthesis, Translation, Vascular smoothmuscle cells, posttranscriptional