Abstract
Through their ability to repress irreversible cell cycle arrest, some transcription factors such as cellular oncogenes are considered as potent repressors of myoblast differentiation. Interestingly, their expression and/or activity are regulated by ligand-dependent transcription factors. Indeed, functional interactions between these proteins are deeply involved in the shift from proliferation to differentiation. Whereas c-Myc efficiently represses myoblast withdrawal from the cell cycle and terminal differentiation, c-Jun exerts a dual myogenic influence. In proliferating cells, it inhibits cell cycle arrest through sequestration of MyoD in a TR/c-Jun/MyoD complex; in parallel, high levels of Jun/Fos AP-1 complexes inhibit MyoD and myogenin expression. At the onset of myoblast differentiation, RXR dissociates the TR/c-Jun/MyoD complex, thus restoring a full MyoD transcriptional activity; in addition, it allows the liganded T3 nuclear receptor to inhibit TPA-inducible AP-1 activity, an event favouring c-Jun/ATF2 formation, a complex stimulating myogenin expression. In addition, inhibition of TPA-inducible AP-1 activity induces the expression of BTG1, a potent coactivator of myogenic factors transcriptional activity. In parallel, RXR expression, through the synthesis of its truncated form addressed into mitochondria, could potentiate the activity of p43, a mitochondrial T3-dependent transcription factor. This results in a stimulation of mitochondrial activity inducing a strong downregulation of c-Myc expression leading to cell cycle arrest and terminal differentiation. Overall, targeting of cellular oncogenes by ligand-dependent transcription factors regulates myoblast withdrawal from the cell cycle. In addition, it appears that RXR has to be considered as a master gene able to reverse the myogenic influence of c-Jun and TR, also involved in a downregulation of c-Myc expression