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.
J Biol Chem
; 289(11): 7264-74, 2014 Mar 14.
Article
em En
| MEDLINE
| ID: mdl-24469459
ABSTRACT
Collagen 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 α-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 post-transcriptional 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.
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Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Ribonucleoproteínas
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Autoantígenos
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Fator de Crescimento Insulin-Like I
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Regulação da Expressão Gênica
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Colágeno Tipo I
Tipo de estudo:
Prognostic_studies
Limite:
Animals
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Humans
Idioma:
En
Revista:
J Biol Chem
Ano de publicação:
2014
Tipo de documento:
Article