Hyperglycemia upregulates translation of the fibroblast growth factor 2 mRNA in mouse aorta via internal ribosome entry site.
Fibroblast growth factor 2 (FGF-2) is normally synthesized at low levels but is elevated in various pathophysiological conditions including diabetes-associated vascular diseases. FGF-2 expression is regulated translationally through an internal ribosome entry site (IRES) located in its mRNA, which allows a nonclassical cap-independent translation. We addressed the pathophysiological regulation of the IRES in vivo by using a streptozotocin-induced hyperglycemic model known to suppress markedly overall translation. Evaluation of FGF-2 IRES-dependent translation was performed with transgenic mice expressing dual luciferase bicistronic mRNA containing the FGF-2 IRES. FGF-2 IRES-dependent reporter activity increased 240% of control in the diabetic aorta although the reporter mRNA levels significantly decreased. Expression of endogenous FGF-2 protein in the aorta closely correlated with the IRES activity but not with FGF-2 mRNA levels. Moreover, the biosynthesis of endogenous FGF-2 protein was stimulated in an IRES-dependent manner by high glucose that significantly suppressed global protein synthesis in aortic smooth muscle cells from the transgenic mice. These results suggest that IRES-dependent translational regulation could play a pathological role in FGF-2 expression in vivo, especially in the cardiovascular consequences of diabetes.
Teshima-Kondo
Shigetada
S
Institut National de la Santé et de la Recherche Médicale U589, Hormones, Facteurs de Croissance et Physiopathologie Vasculaire, Institut Louis Bugnard IFR31, Hôpital Rangueil, Toulouse, France.
Kondo
Kazumi
K
Prado-Lourenco
Leonel
L
Gonzalez-Herrera
Irma Gabriela
IG
Rokutan
Kazuhito
K
Bayard
Francis
F
Arnal
Jean-François
JF
Prats
Anne-Catherine
AC
D000818:Animals; D001011:Aorta / Q000378:metabolism*; D001665:Binding Sites; D016222:Fibroblast Growth Factor 2 / Q000096:biosynthesis* / Q000235:genetics*; D005947:Glucose / Q000494:pharmacology; D006943:Hyperglycemia / Q000235:genetics*; D051379:Mice; D009928:Organ Specificity; D014176:Protein Biosynthesis / Q000187:drug effects / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012270:Ribosomes / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D013379:Substrate Specificity; D015854:Up-Regulation / Q000187:drug effects
D012333:RNA, Messenger; D016222:Fibroblast Growth Factor 2; D005947:Glucose