Tesis doctoral de Emilie Marie Veronique Bigaud
Methylthioadenosine phosphorylase (mtap) catalyzes the hydrolysis of methylthioadenosine (mta), and it has been implicated in pivotal cellular processes. Deletion of mtap has been commonly reported in different cancer types and deregulation of this enzyme has been associated with the progression of liver injury. The aim of this study was to investigate the molecular mechanisms triggered by mtap deficiency that participate in the progression of liver disorders. mice with mtap deficiency displayed increased sensitivity upon challenging with ccl4. The differential phenotype of mtap+/- mice is likely due to a twofold accumulation of mta in hepatocytes. To characterize the mechanisms involved, the proteome of mtap deficient sk-hep1 and sk-hep1mtap+ cells that exhibit a twofold decrease in mta levels, were compared. Itraq analysis was performed resulting in the identification of 216 differential proteins (p<0.05) that suggest deregulation of cellular pathways as those mediated by erk or nfkb. Moreover, our results suggest that protein-methylation profile is significantly modified upon accumulation of mta, a well-known inhibitor of prmts. The differential protein methylation analysis was performed via ip-lc-ms/ms and analyzed using mascot. As expected, there was a significant increase on protein methylation in sk-hep1+ cells. The identified methyl-proteins include 47 non-described r-methylation sites on proteins that were mainly involved in cell proliferation, rna processing and protein synthesis. our data support that mtap deficiency leads to mta accumulation and deregulation of central cellular pathways, increasing proliferation and decreasing the susceptibility to quimiotherapeutic drugs, in part due to differential protein methylation.
Datos académicos de la tesis doctoral «Caracterización de los mecanismos implicados en las alteraciones fisiopatológicas inducidas por una deficiencia de metiltioadenosina fosforilasa en células hepáticas«
- Título de la tesis: Caracterización de los mecanismos implicados en las alteraciones fisiopatológicas inducidas por una deficiencia de metiltioadenosina fosforilasa en células hepáticas
- Autor: Emilie Marie Veronique Bigaud
- Universidad: Navarra
- Fecha de lectura de la tesis: 12/03/2015
Dirección y tribunal
- Director de la tesis
- Fernando Jose Corrales Izquierdo
- Tribunal
- Presidente del tribunal: concepcion Gil garcia
- Manuel mateo Sánchez del pino (vocal)
- felix Elortza basterrika (vocal)
- matías Antonio ávila zaragozá (vocal)