The 2'-5' oligoadenylate/RNase L/RNase L inhibitor pathway regulates both MyoD mRNA stability and muscle cell differentiation.
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.
Bisbal
C
C
EP 2030 and UMR 5535 CNRS, 34293 Montpellier Cedex 5, France. bisbal@jones.igm.cnrs-mop.fr
Silhol
M
M
Laubenthal
H
H
Kaluza
T
T
Carnac
G
G
Milligan
L
L
Le Roy
F
F
Salehzada
T
T
D018528:ATP-Binding Cassette Transporters; D000818:Animals; D002454:Cell Differentiation / Q000235:genetics; D002478:Cells, Cultured; D018833:Chaperonins; D016373:DNA, Antisense; D004722:Endoribonucleases / Q000235:genetics / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000378:metabolism; D005786:Gene Expression Regulation; D006207:Half-Life; D007544:Isopropyl Thiogalactoside / Q000494:pharmacology; D051379:Mice; D018482:Muscle, Skeletal / Q000166:cytology / Q000378:metabolism*; D017570:MyoD Protein / Q000187:drug effects / Q000235:genetics* / Q000378:metabolism; D018008:Myogenin / Q000235:genetics / Q000378:metabolism; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D020871:RNA Stability; D012333:RNA, Messenger / Q000737:chemistry / Q000378:metabolism*; D014162:Transfection
D018528:ATP-Binding Cassette Transporters; C501918:Abce1 protein, mouse; D016373:DNA, Antisense; D004791:Enzyme Inhibitors; D017570:MyoD Protein; C503801:Myog protein, mouse; D018008:Myogenin; D011506:Proteins; D012333:RNA, Messenger; D007544:Isopropyl Thiogalactoside; D004722:Endoribonucleases; C031956:2-5A-dependent ribonuclease; D018833:Chaperonins