RESUMEN
Following genotoxic stress, cells activate a complex signalling network to arrest the cell cycle and initiate DNA repair or apoptosis. The tumour suppressor p53 lies at the heart of this DNA damage response. However, it remains incompletely understood, which signalling molecules dictate the choice between these different cellular outcomes. Here, we identify the transcriptional regulator apoptosis-antagonizing transcription factor (AATF)/Che-1 as a critical regulator of the cellular outcome of the p53 response. Upon genotoxic stress, AATF is phosphorylated by the checkpoint kinase MK2. Phosphorylation results in the release of AATF from cytoplasmic MRLC3 and subsequent nuclear translocation where AATF binds to the PUMA, BAX and BAK promoter regions to repress p53-driven expression of these pro-apoptotic genes. In xenograft experiments, mice exhibit a dramatically enhanced response of AATF-depleted tumours following genotoxic chemotherapy with adriamycin. The exogenous expression of a phospho-mimicking AATF point mutant results in marked adriamycin resistance in vivo. Nuclear AATF enrichment appears to be selected for in p53-proficient endometrial cancers. Furthermore, focal copy number gains at the AATF locus in neuroblastoma, which is known to be almost exclusively p53-proficient, correlate with an adverse prognosis and reduced overall survival. These data identify the p38/MK2/AATF signalling module as a critical repressor of p53-driven apoptosis and commend this pathway as a target for DNA damage-sensitizing therapeutic regimens.
Asunto(s)
Proteínas Reguladoras de la Apoptosis/fisiología , Apoptosis/fisiología , Daño del ADN/fisiología , Proteínas Represoras/fisiología , Proteína p53 Supresora de Tumor/fisiología , Transporte Activo de Núcleo Celular , Secuencia de Aminoácidos , Animales , Proteínas Reguladoras de la Apoptosis/genética , Puntos de Control del Ciclo Celular , Daño del ADN/genética , Doxorrubicina/farmacología , Resistencia a Antineoplásicos/genética , Neoplasias Endometriales/genética , Femenino , Amplificación de Genes , Dosificación de Gen , Células HEK293 , Humanos , Ratones , Datos de Secuencia Molecular , Complejos Multiproteicos , Cadenas Ligeras de Miosina/metabolismo , Neuroblastoma/genética , Neuroblastoma/mortalidad , Presión Osmótica , Fosforilación , Pronóstico , Procesamiento Proteico-Postraduccional , Proteínas Represoras/genéticaRESUMEN
Allogeneic hematopoietic stem cell transplantation and solid organ transplantation have become established treatments offered to patients for whom there are otherwise no curative treatment options. Unfortunately, these therapeutic modalities are associated with severe complications that limit its applicability. Alloimmunity is an important cause of morbidity and mortality after both organ transplantation and allogeneic hematopoietic stem cell transplantation and represents a major barrier to the more wide-spread use of these treatment modalities. Statins are a class of lipid-lowering drugs, which also posses immunomodulatory effects. Results from preclinial research and early-stage clinical studies indicate that treatment with statins could be beneficial for the prevention and treatment of graft-versus-host disease and transplant rejection. In addition to preventing graft-versus-host disease or graft rejection statins possess several other effects that might prove beneficial in the setting of transplantation, such as cardiovascular protection and antineoplastic activity. Here we summarize the current knowledge about the immunomodulatory effects of statins and discuss the clinical implications for their use in patients undergoing stem cell transplantation or solid organ transplantation.