The 2′-5′ oligoadenylate/RNase L/RNase L inhibitor pathway regulates both MyoD mRNA stability and muscle cell differentiation

Bisbal, C.; Silhol, M.; Laubenthal, H.; Kaluza, T.; Carnac, G.; Milligan, L.; Le Roy, F.; Salehzada, T.

Mol Cell Biol

2000-07 / vol 20 / pages 4959-69


The 2′-5′ oligoadenylate (2-5A)/RNase L pathway is one of the enzymatic pathways induced by interferon. RNase L is a latent endoribonuclease which is activated by 2-5A and inhibited by a specific protein known as RLI (RNase L inhibitor). This system has an important role in regulating viral infection. Additionally, variations in RNase L activity have been observed during cell growth and differentiation but the significance of the 2-5A/RNase L/RLI pathway in these latter processes is not known. To determine the roles of RNase L and RLI in muscle differentiation, C2 mouse myoblasts were transfected with sense and antisense RLI cDNA constructs. Importantly, the overexpression of RLI in C2 cells was associated with diminished RNase L activity, an increased level of MyoD mRNA, and accelerated kinetics of muscle differentiation. Inversely, transfection of the RLI antisense construct was associated with increased RNase L activity, a diminished level of MyoD mRNA, and delayed differentiation. In agreement with these data, MyoD mRNA levels were also decreased in C2 cells transfected with an inducible RNase L construct. The effect of RNase L activity on MyoD mRNA levels was relatively specific because expression of several other mRNAs was not altered in C2 transfectants. Therefore, RNase L is directly involved in myoblast differentiation, probably through its role in regulating MyoD stability. This is the first identification of a potential mRNA target for RNase L.

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Animals; Cells, Cultured; Mice; RNA Stability; Gene Expression Regulation; Transfection; Myogenin/genetics/metabolism; Half-Life; Endoribonucleases/genetics/*metabolism; Cell Differentiation/genetics; *ATP-Binding Cassette Transporters; *Chaperonins; DNA, Antisense; Enzyme Inhibitors/metabolism; Isopropyl Thiogalactoside/pharmacology; Muscle, Skeletal/cytology/*metabolism; MyoD Protein/drug effects/*genetics/metabolism; Proteins/genetics/*metabolism; RNA, Messenger/chemistry/*metabolism

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