IRES-dependent regulation of FGF-2 mRNA translation in pathophysiological conditions in the mouse.
The mRNA coding for FGF-2 (fibroblast growth factor 2), a major angiogenic factor, is translated by an IRES (internal ribosome entry site)-dependent mechanism. We have studied the role of the IRES in the regulation of FGF-2 expression in vivo, under pathophysiological conditions, by creating transgenic mice lines expressing bioluminescent bicistronic transgenes. Analysis of FGF-2 IRES activity indicates strong tissue specificity in adult brain and testis, suggesting a role of the IRES in the activation of FGF-2 expression in testis maturation and brain function. We have explored translational control of FGF-2 mRNA under diabetic hyperglycaemic conditions, as FGF-2 is implied in diabetes-related vascular complications. FGF-2 IRES is specifically activated in the aorta wall in streptozotocin-induced diabetic mice, in correlation with increased expression of endogenous FGF-2. Thus, under hyperglycaemic conditions, where cap-dependent translation is blocked, IRES activation participates in FGF-2 overexpression, which is one of the keys of diabetes-linked atherosclerosis aggravation. IRES activation under such pathophysiological conditions may involve ITAFs (IRES trans-acting factors), such as p53 or hnRNP AI (heterogeneous nuclear ribonucleoprotein AI), recently identified as inhibitory or activatory ITAFs respectively for FGF-2 IRES.
Gonzalez-Herrera
I G
IG
Institut National de la Santé et de la Recherche Médicale U589, "Hormones, facteurs de croissance et physiopathologie vasculaire", Institut Louis Bugnard, IFR31, CHU Rangueil, Bâtiment L3, Avenue Jean Poulhès, BP 84225, 31432 Toulouse Cedex 4, France.
Prado-Lourenco
L
L
Teshima-Kondo
S
S
Kondo
K
K
Cabon
F
F
Arnal
J-F
JF
Bayard
F
F
Prats
A-C
AC
D000818:Animals; D001808:Blood Vessels / Q000378:metabolism / Q000473:pathology; D018387:Codon, Initiator; D003920:Diabetes Mellitus / Q000235:genetics / Q000378:metabolism; D016222:Fibroblast Growth Factor 2 / Q000235:genetics* / Q000378:metabolism; D005786:Gene Expression Regulation; D051379:Mice; D008822:Mice, Transgenic; D010442:Peptide Chain Initiation, Translational; D014176:Protein Biosynthesis; D012270:Ribosomes / Q000378:metabolism
D018387:Codon, Initiator; D016222:Fibroblast Growth Factor 2