Caracterización de los mecanismos implicados en las alteraciones fisiopatológicas inducidas por una deficiencia de metiltioadenosina fosforilasa en células hepáticas
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...
Main Authors: | , |
---|---|
Format: | info:eu-repo/semantics/doctoralThesis |
Language: | spa |
Published: |
Servicio de Publicaciones de la Universidad de Navarra
2015
|
Subjects: | |
Online Access: | https://hdl.handle.net/10171/38418 |
_version_ | 1793400499932758016 |
---|---|
author | Bigaud, E. (Emilie) Corrales, F.J. (Fernando José) |
author_facet | Bigaud, E. (Emilie) Corrales, F.J. (Fernando José) |
author_sort | Bigaud, E. (Emilie) |
collection | DSpace |
description | 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. |
format | info:eu-repo/semantics/doctoralThesis |
id | oai:dadun.unav.edu:10171-38418 |
institution | Universidad de Navarra |
language | spa |
publishDate | 2015 |
publisher | Servicio de Publicaciones de la Universidad de Navarra |
record_format | dspace |
spelling | oai:dadun.unav.edu:10171-384182020-03-03T11:26:18Z Caracterización de los mecanismos implicados en las alteraciones fisiopatológicas inducidas por una deficiencia de metiltioadenosina fosforilasa en células hepáticas Bigaud, E. (Emilie) Corrales, F.J. (Fernando José) Metabolismo intermediario Proteínas Peptidos Biología celular Materias Investigacion::Ciencias de la vida::Biología 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. 2015-05-22T12:05:43Z 2015-05-22T12:05:43Z 2015 2015-03-12 info:eu-repo/semantics/doctoralThesis https://hdl.handle.net/10171/38418 spa info:eu-repo/semantics/openAccess application/pdf Servicio de Publicaciones de la Universidad de Navarra |
spellingShingle | Metabolismo intermediario Proteínas Peptidos Biología celular Materias Investigacion::Ciencias de la vida::Biología Bigaud, E. (Emilie) Corrales, F.J. (Fernando José) Caracterización de los mecanismos implicados en las alteraciones fisiopatológicas inducidas por una deficiencia de metiltioadenosina fosforilasa en células hepáticas |
title | Caracterización de los mecanismos implicados en las alteraciones fisiopatológicas inducidas por una deficiencia de metiltioadenosina fosforilasa en células hepáticas |
title_full | Caracterización de los mecanismos implicados en las alteraciones fisiopatológicas inducidas por una deficiencia de metiltioadenosina fosforilasa en células hepáticas |
title_fullStr | Caracterización de los mecanismos implicados en las alteraciones fisiopatológicas inducidas por una deficiencia de metiltioadenosina fosforilasa en células hepáticas |
title_full_unstemmed | Caracterización de los mecanismos implicados en las alteraciones fisiopatológicas inducidas por una deficiencia de metiltioadenosina fosforilasa en células hepáticas |
title_short | Caracterización de los mecanismos implicados en las alteraciones fisiopatológicas inducidas por una deficiencia de metiltioadenosina fosforilasa en células hepáticas |
title_sort | caracterización de los mecanismos implicados en las alteraciones fisiopatológicas inducidas por una deficiencia de metiltioadenosina fosforilasa en células hepáticas |
topic | Metabolismo intermediario Proteínas Peptidos Biología celular Materias Investigacion::Ciencias de la vida::Biología |
url | https://hdl.handle.net/10171/38418 |
work_keys_str_mv | AT bigaudeemilie caracterizaciondelosmecanismosimplicadosenlasalteracionesfisiopatologicasinducidasporunadeficienciademetiltioadenosinafosforilasaencelulashepaticas AT corralesfjfernandojose caracterizaciondelosmecanismosimplicadosenlasalteracionesfisiopatologicasinducidasporunadeficienciademetiltioadenosinafosforilasaencelulashepaticas |