RESUMO
Since the discovery of the myc gene, few genes are likely to have such influence on biomedical research. The diversity of the biological functions regulated by this transcription factor and its impact in human health have attracted investigators from many different fields. The development of conditional knockout mouse models has allowed for the characterization of Myc-driven molecular mechanisms in primary cells in physiological and pathological conditions. In this review, we discuss some of the main functions and recent findings regarding c-Myc in in vivo B lymphocyte differentiation from early progenitors to terminally differentiated cells.
Assuntos
Linfócitos B/citologia , Linfócitos B/metabolismo , Diferenciação Celular , Proteínas Proto-Oncogênicas c-myc/metabolismo , Animais , Humanos , Proto-Oncogene Mas , Proteínas Proto-Oncogênicas c-myc/deficiência , Proteínas Proto-Oncogênicas c-myc/genéticaRESUMO
p73 is a novel member of the p53 family of tumor suppressor proteins which is involved in cellular differentiation, tumor suppression, and the response to genotoxic stress. The molecular mechanisms regulating p73 activity are still poorly understood. Recently, p73 was found to be a target of the enzymatic activity of c-Abl, a non-receptor tyrosine kinase that potently activated in response to DNA damage. Here, we present evidence that c-Abl induces the phosphorylation of p73 in threonine residues adjacent to prolines, and that the p38 MAP kinase pathway mediates this response. Furthermore, we found that activation of p38 is sufficient to enhance the stability of p73, and that the transcriptional activation of p73 by c-Abl requires the activity of p38. These findings indicate that members of the MAP kinases superfamily of signaling molecules can regulate p73, and support a role for the p38 MAP kinase in a novel biochemical pathway by which c-Abl regulates this p53-related molecule.
Assuntos
Proteínas de Ligação a DNA/metabolismo , Genes abl , Sistema de Sinalização das MAP Quinases , Proteínas Quinases Ativadas por Mitógeno/fisiologia , Proteínas Nucleares/metabolismo , Processamento de Proteína Pós-Traducional/fisiologia , Proteínas Proto-Oncogênicas c-abl/fisiologia , Neoplasias Ósseas/patologia , Proteínas Quinases Dependentes de Cálcio-Calmodulina/metabolismo , Linhagem Celular , Proteínas de Ligação a DNA/genética , Ativação Enzimática , Inibidores Enzimáticos/farmacologia , Células Epiteliais/metabolismo , Genes Supressores de Tumor , Humanos , Imidazóis/farmacologia , Proteínas Quinases JNK Ativadas por Mitógeno , Rim , MAP Quinase Quinase 1 , MAP Quinase Quinase 6 , MAP Quinase Quinase 7 , Quinases de Proteína Quinase Ativadas por Mitógeno/metabolismo , Proteínas Quinases Ativadas por Mitógeno/antagonistas & inibidores , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Família Multigênica , Proteínas Nucleares/genética , Osteossarcoma/patologia , Fosforilação , Fosfosserina/metabolismo , Fosfotirosina/metabolismo , Prolina/química , Processamento de Proteína Pós-Traducional/genética , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Tirosina Quinases/metabolismo , Piridinas/farmacologia , Proteínas Recombinantes de Fusão/fisiologia , Transcrição Gênica , Transfecção , Células Tumorais Cultivadas , Proteína Tumoral p73 , Proteínas Supressoras de Tumor , Proteínas Quinases p38 Ativadas por Mitógeno , Domínios de Homologia de srcRESUMO
In order to investigate the molecular mechanisms implicated in the induction of chemo sensitivity by adenovirus E1a gene expression, we decided to investigate which signal transduction pathways could be affected by the E1a gene in Human Normal Fibroblast (IMR90). No effect was observed in SAPK pathways (p38MAPK and JNK), but E1a was able to affect the Akt activation mediated by insulin. This result was confirmed by transient transfection experiments performed in Cos-7 cells and also observed in other transformed cell lines such as A431. Furthermore, E1a expression induces a decrease in the basal status of Akt activity. Finally we demonstrated that E1a is able to block the Akt activation mediated by cisplatin and correlates with a sensitive phenotype. In summary, our data demonstrate that specific inhibition of the PI3K/Akt pathway mediates some of the biological properties of E1a such as induction of chemosensitivity.