Transcription factors and muscle differentiation
Résumé
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