UP-REGULATION OF INSULIN-LIKE-GROWTH-FACTOR BINDING PROTEIN-5 IS INDEPENDENT OF MUSCLE-CELL DIFFERENTIATION, SENSITIVE TO RAPAMYCIN, BUT INSENSITIVE TO WORTMANNIN AND LY294002
S. Rousse et al., UP-REGULATION OF INSULIN-LIKE-GROWTH-FACTOR BINDING PROTEIN-5 IS INDEPENDENT OF MUSCLE-CELL DIFFERENTIATION, SENSITIVE TO RAPAMYCIN, BUT INSENSITIVE TO WORTMANNIN AND LY294002, Endocrinology, 139(4), 1998, pp. 1487-1493
Skeletal myoblast differentiation is stimulated by insulin-like growth
factors (IGFs). The autocrine action of IGFs is mediated through the
type-1 IGF receptor (IGFR-1) and modulated by IGF binding proteins (IG
FBPs) secreted by the cells. The mouse C2 myoblast cell line stably tr
ansfected with a vector producing IGF-II antisense RNA was used to sho
w that specific IGFBP expression changes with the state of the cells:
high levels of IGFBP-2 messenger RNA (mRNA) were found only in prolife
rating myoblasts, whereas IGFBP-3 mRNA was induced in quiescent cells.
Secretion of IGFBP5 was strongly stimulated during differentiation. I
nsulin and IGF dose-response experiments showed that up-regulation of
IGFBP-5 resulted from IGFR-1 activation. Drugs interfering with IGFR-1
signaling and inhibiting myoblast differentiation had different effec
ts on IGFBP-5 up-regulation. Two phosphatidylinositol 3-kinase (PI 3-k
inase) inhibitors, wortmaninn and LY294002 2-(4-morpholinyl)-8-phenyl-
4H-1-benzopyran-4-one], failed to alter IGFBP-5 up-regulation, which p
ersisted in the absence of differentiation. Rapamycin which indirectly
prevents activation of the p70 ribosomal protein-S6 kinase (p70(S6k))
, suppressed IGFBP-5 induction. Because the PI3-kinase inhibitors bloc
k p70(S6k), neither kinase would be required for IGFR-1-dependent IGFB
P-5 induction. In C2 anti-IGF-II myoblasts, IGFBP-5 induction is there
fore rapamycin-sensitive and independent of differentiation.