Titre : | P16 promotes premature senescence of DM1 myoblasts |
contenu dans : | |
Auteurs : | Congrès international de myologie 2008 (International Congress of Myology 2008; 26-30 mai 2008; Marseille, France) ; Gasnier E ; Bigot A ; Mouly V ; Furling D |
Type de document : | Article |
Année de publication : | 2008 |
Pages : | p. 248 |
Langues: | Anglais |
Résumé : | Myotonic Dystrophy type I (DM1) is caused by a CTG expansion in the 3’-UTR of the DMPK gene and is characterized by progressive muscle weakness and wasting. Large CTG repeats affect the differentiation program and we have showed that the proliferative capacity of the cDM1 myoblasts was significantly reduced when compared to non-affected cells. DM1 myoblasts have not exhausted their proliferative capacity but have a premature replicative arrest. Analysis of several markers suggests that a mechanism of premature senescence triggers this early arrest. We found that an early accumulation of the cdk inhibitor p16 is associated with this phenotype in DM1 cells. We show that an inactivation of p16 activity in DM1 myoblasts was able to inhibit premature senescence and to restore proliferative capacity : DM1 cells overexpressing CdK4 that binds and inhibits p16, can make the same number of division as control cells. Our results also indicate that the accelerated telomere shortening measured in DM1 satellite cells may not contribute to the aberrant induction of p16. We propose that deregulation of the mitotic clock is a consequence of a stress related to the amplified CTG repeat that promotes premature senescence mediating by a p16-dependent mechanism in DM1 muscle cell precursors. The mechanism of p16 regulation in the DM1 cells is currently under investigation in order to determine how the CTG mutation interferes with the p16 pathway. |