MEF2C belongs to the family of Myocyte Enhancer Factor 2 transcription factors, which activate the muscle-specific gene expression program. Its activity is finely modulated at several levels but some aspects of this regulation still remains uncharacterized; for example, MEF2C is already expressed in proliferating myoblasts, but it is transcriptionally silent unless the cells are stimulated to withdraw the cell cycle and differentiate. Phosphorylation of MEF2 factors at so-called Ser/Thr-Pro motifs can modulate protein function through the induction of conformational changes by the peptidyl–prolyl cis/trans isomerase Pin1. This regulatory mechanism is based on the physical interaction between Pin1 and the Ser98 and Ser110 phosphoacceptor sites located in the alternative spliced exon α1 of MEF2C. The MEF2C/Pin1 interaction results in the repression of MEF2C stability and transcriptional activity, inhibiting muscle differentiation. We investigated the function of this regulatory mechanism in primary myogenic stem cells (SCs) combining the analysis of the dynamics of MEF2C phosphorylation with the study of the alternative splicing pattern. We demonstrated that the conditions necessary for the interaction between MEF2C and Pin1 are satisfied exclusively in proliferating SCs, where: Pin1 expression is upregulated MEF2C isoform containing the exon α1 specifically appears in response to activation signals MEF2C phosphorylation on the Pin1-binding sites occurs specifically in proliferating SCs Indeed we showed that MEF2C and Pin1 can interact in the nuclei of C2C7 and SCs-derived myoblasts. Overall we provide evidence that this interaction not only would serve as a failsafe mechanism to keep silent the MEF2C-dependent transcription of muscle specific genes in proliferating SCs but we hypothesize that the expression of the MEF2Cα1 isoform phosphorylated on Ser98 and Ser110 and the interaction with Pin1 might actively contribute to promote SCs proliferation, allowing the expansion of the activated SCs pool and avoiding their premature differentiation.
A POTENTIAL ROLE OF MEF2C IN THE MYOGENIC PROGRESSION BESIDE TERMINAL DIFFERENTIATION / Baruffaldi, Fiorenza; Badodi, Sara; Ganassi, Massimo; Angelelli, Cecilia; Magli, Alessandro; Margaret Buckingham, Didier Montarras; Molinari, Susanna. - (2012), pp. 1-26.
|Data di pubblicazione:||2012|
|Titolo:||A POTENTIAL ROLE OF MEF2C IN THE MYOGENIC PROGRESSION BESIDE TERMINAL DIFFERENTIATION|
|Autore/i:||Baruffaldi, Fiorenza; Badodi, Sara; Ganassi, Massimo; Angelelli, Cecilia; Magli, Alessandro; Margaret Buckingham, Didier Montarras; Molinari, Susanna|
|Data del convegno:||aprile 2012|
|Luogo del convegno:||Sitges (Barcelona) Spain|
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