RESUMO
The members of the SR family of splicing regulators were initially characterized for their critical roles in constitutive and regulated splicing. They are implicated in different aspects of gene expression processes, including transcription, RNA stability, mRNA transport, and translational control. While knockout studies have demonstrated their essential functions during animal development, the pathway(s) leading to a specific cellular phenotype remains poorly understood. We report here that the SR protein SC35 controls cell proliferation during pituitary gland development but is completely dispensable in terminal differentiated mature cardiomyocytes in mice. We show that loss of SC35 in mouse embryonic fibroblasts induces G2/M cell cycle arrest and genomic instability, resulting at least in part from p53 hyperphosphorylation and hyperacetylation. While p53 hyperphosphorylation appears related to ATM activation, its hyperacetylation has been attributed to the increased expression of the acetyltransferase gene p300 and the aberrant splicing of the deacetylase gene SirT1. These findings reveal the involvement of SC35 in specific pathways in regulating cell proliferation and genomic stability during mammalian organogenesis and suggest its potential function in tumorigenesis.
Assuntos
Instabilidade Genômica , Proteínas Nucleares/metabolismo , Organogênese , Ribonucleoproteínas/metabolismo , Animais , Diferenciação Celular , Divisão Celular , Proliferação de Células , Embrião de Mamíferos/citologia , Embrião de Mamíferos/metabolismo , Fibroblastos/citologia , Fibroblastos/metabolismo , Fase G2 , Teste de Complementação Genética , Camundongos , Camundongos Knockout , Miócitos Cardíacos/citologia , Proteínas Nucleares/deficiência , Hipófise/anormalidades , Hipófise/citologia , Hipófise/embriologia , Ribonucleoproteínas/deficiência , Fatores de Processamento de Serina-Arginina , Proteína Supressora de Tumor p53/metabolismoRESUMO
A function of the transcription factor REST is to block the expression of neuronal phenotypic traits in non-neuronal cells. Previous studies have shown that REST-mediated repression requires histone deacetylase activity and that recruitment of deacetylases is mediated by two co-repressors, Sin3A and CoREST. In this study, we show that a repressor domain in CoREST interacts with BRG1-associated factor (BAF) 57, a component of the hSWI.SNF complex. In vivo, BAF57 occupies the neuronal sodium channel gene (Nav1.2) promoter, and targeting to this gene requires REST. In addition to BAF57, the ATPase BRG1 and BAF170, other members of the hSWI.SNF complex, are also present in the REST.CoREST repressor complex. Microinjection of specific antibodies against BRG1, BAF57, or BAF170 into Rat1 fibroblasts relieves repression of RE1 reporter genes. Together, our data suggest that ATP-dependent chromatin remodeling, as well as histone deacetylation, is needed for REST-mediated repression.