Inhibition of mammalian target of rapamycin (mTOR) signalling in C2C12 myoblasts prevents myogenic differentiation without affecting the hyperphosphorylation of 4E-BP1

Willett, Mark, Cowan, Joanne L., Vlasak, Markete, Coldwell, Mark J. and Morley, Simon J. (2009) Inhibition of mammalian target of rapamycin (mTOR) signalling in C2C12 myoblasts prevents myogenic differentiation without affecting the hyperphosphorylation of 4E-BP1. Cellular Signalling, 21 (10), 1504-1512. (doi:10.1016/j.cellsig.2009.05.009). (PMID:19481146)

Abstract

Current accepted models suggest that hypophosphorylated 4E-binding protein (4E-BP1) binds to initiation
factor 4E (eIF4E) to inhibit cap-dependent translation, a process readily reversed by its phosphorylation
following activation of mammalian target of rapamycin (mTORC1) signalling. Myogenic differentiation in the
C2C12 myoblast model system reflects a concerted and controlled activation of transcription and translation
following the exit of cells from the cell cycle. Here we show that myogenic differentiation is associated with
increased rates of translation, the up-regulation of both 4E-BP1 mRNA and protein levels and enhanced levels
of eIF4E/4E-BP1 complex. Paradoxically, treatment of C2C12 myoblasts with an inhibitor of mTOR signalling
(RAD001) which inhibits translation, promotes the hyperphosphorylation of 4E-BP1 on novel sites and
prevents the increase in 4E-BP1 levels. In contrast, eIF4E appears to be under translational control with a
significant delay between induction of mRNA and subsequent protein expression.

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Contributors

Author: Mark J. Coldwell

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