RESUMEN
Steroidogenic factor-1 (SF-1/Ad4BP; NR5A1), a nuclear receptor transcription factor, has a pivotal role in adrenal and gonadal development in humans and mice. A frequent feature of childhood adrenocortical tumors is SF-1 amplification and overexpression. Here we show that an increased SF-1 dosage can by itself augment human adrenocortical cell proliferation through concerted actions on the cell cycle and apoptosis. This effect is dependent on an intact SF-1 transcriptional activity. Gene expression profiling showed that an increased SF-1 dosage regulates transcripts involved in steroid metabolism, the cell cycle, apoptosis, and cell adhesion to the extracellular matrix. Consistent with these results, increased SF-1 levels selectively modulate the steroid secretion profile of adrenocortical cells, reducing cortisol and aldosterone production and maintaining dehydroepiandrosterone sulfate secretion. As a model to understand the mechanisms of transcriptional regulation by increased SF-1 dosage, we studied FATE1, coding for a cancer-testis antigen implicated in the control of cell proliferation. Increased SF-1 levels increase its binding to a consensus site in FATE1 promoter and stimulate its activity through modulation of the recruitment of specific cofactors. On the other hand, sphingosine, which can compete with phospholipids for binding to SF-1, had no effect on the SF-1 dosage-dependent increase of adrenocortical cell proliferation and expression of the FATE1 promoter. In mice, increased Sf-1 dosage produces adrenocortical hyperplasia and formation of tumors expressing gonadal markers (Amh, Gata-4), which originate from the subcapsular region of the adrenal cortex. Gene expression profiling revealed that genes involved in cell adhesion and the immune response and transcription factor signal transducer and activator of transcription-3 (Stat3) are differentially expressed in Sf-1 transgenic mouse adrenals compared with wild-type adrenals. Our studies reveal a critical role for SF-1 dosage in adrenocortical tumorigenesis and constitute a rationale for the development of drugs targeting SF-1 transcriptional activity for adrenocortical tumor therapy.
Asunto(s)
Regulación Neoplásica de la Expresión Génica , Neoplasias/metabolismo , Neoplasias/patología , Factor Esteroidogénico 1/metabolismo , Animales , Secuencia de Bases , Sitios de Unión , Adhesión Celular , Línea Celular Tumoral , Proliferación Celular , Transformación Celular Neoplásica/genética , Transformación Celular Neoplásica/metabolismo , Transformación Celular Neoplásica/patología , Matriz Extracelular/metabolismo , Histidina/genética , Histidina/metabolismo , Humanos , Metabolismo de los Lípidos , Ratones , Ratones Transgénicos , Datos de Secuencia Molecular , Mutación/genética , Neoplasias/genética , Factor de Transcripción STAT3/metabolismo , Transducción de Señal , Factor Esteroidogénico 1/genética , Esteroides/metabolismo , Transcripción Genética/genética , Regulación hacia ArribaRESUMEN
Southern Brazil has one of the highest incidences of childhood adrenocortical tumors (ACTs), occurring 10-15 times more frequently than worldwide estimates. The reasons for this increase remain elusive. In an attempt to further characterize the genetic changes in childhood ACTs, we recently detected a consistent gain of 9q (or a portion of it) in eight of nine cases of pediatric ACTs and amplification of 9q34 in the majority of these cases using comparative genomic hybridization. Other studies involving both childhood and adult ACTs have corroborated these findings. To follow up on these results, we examined whether the steroidogenic factor 1 (SF-1) gene, which is located in this chromosomal region and plays an important role in the development and function of the adrenal cortex is amplified in these ACT cases. We detected increased copy number of the SF-1 gene in all eight cases with 9q gain, suggesting an association between an increased copy number of the SF-1 gene and adrenocortical tumorigenesis.
Asunto(s)
Neoplasias de la Corteza Suprarrenal/genética , Cromosomas Humanos Par 9/genética , Proteínas de Unión al ADN/genética , Amplificación de Genes , Factores de Transcripción/genética , Adolescente , Neoplasias de la Corteza Suprarrenal/epidemiología , Brasil/epidemiología , Niño , Mapeo Cromosómico , Proteínas de Homeodominio , Humanos , Incidencia , Receptores Citoplasmáticos y Nucleares , Factor Esteroidogénico 1RESUMEN
A sessão de pôster é a forma mais comum de apresentação de trabalhos e pesquisas em encontros científicos médicos, e, apesar disso, são escassas as informações sobre este tema na literatura médica. Desde o planejamento, é importante traçar prazos realistas, seguir as instruções fornecidas pelos organizadores do evento e se preparar de acordo com a audiência. O pôster contém um cabeçalho e o texto, que inclui: resumo, introdução, material e métodos, discussão, conclusões e referências. O estilo e o tamanho das fontes devem possibilitar a leitura a uma distância de 1 a 2 metros. Em algumas situações, figuras, gráficos e tabelas no pôster podem apresentar certas informações mais claramente e em menor espaço do que se descritas sob a forma de texto. Bom planejamento e treinamento diminuem eventuais dificuldades na apresentação do pôster. Este trabalho revisa o assunto, trazendo informações objetivas sobre este método.
Posters are the most common form of presentation of scientific works in medical meetings. In spite of their importance however there is very little information about this issue available in the medical literature. It is important to plan since the beginning, to set a realistic time schedule, to follow the instructions provided by the organizers of the meeting and to prepare oneself according to the audience. The poster contains a title and a text including abstract, introduction, method, results, discussion, conclusions and references. Font and size used should allow reading from a 1 to 2 meters distance. In some situations, certain kind of information is presented more clearly and occupying less space in form of tables, graphs, and figures than in form of a text. Good planning and training diminish possible difficulties during the poster presentation. This paper reviews the subject and provides objective information on the advantages of this method.