INFORMAZIONI SU
BARUFFALDI ALMA
 |
Supervisore: Dr.ssa Maestro Twist1/MDM2 interplay in the pathogenesis of sarcomas |
| Twist proteins are a transcription factor that includes two members, Twist1 and Twist2, known for their involvement in mesodermal development during embryogenesis. Twist proteins have been shown to contribute to cancer development and progression favouring epithelial-mesenchymal transition, particularly in carcinomas, and by promoting the bypass of cellular safeguard programs. Our research group has found that Twist1 is overexpressed in various sarcoma histotypes. In most of these tumors, p53 is retained wild-type and is inactivated by an alternative mechanism to p53 mutation. Indeed, our group has found that Twist1, by binding directly to p53, induces its inactivation by preventing key phosphorylations and facilitating its degradation. Furthermore, in these last years, our group collected evidence that Twist1 interacts not only with p53 but also with MDM2, forming a trimeric complex that leads to reduced therapeutic efficacy of MDM2 inhibitors. When Twist1/MDM2 binding was examined, it was found that MDM2 does not appear to affect Twist1 protein levels. In investigating the subcellular localization of this trimeric complex, we found that Twist1 appears to localize be localized in nuclear bodies/nucleoli, suggesting a possible role of Twist1 in the nuclear export of MDM2. The aim of this project is to investigate in better detail Twist1/ MDM2 interplay, focusing on the MDM2/Twist1 trascriptional and post-trascriptional regulation and furthermore on Twist1/ARF/MDM2/PML shuttle, particularly in the pathogenesis of sarcomas. | |