RESUMEN

Interference of Ras signaling deregulates thymocyte development in mouse models. However, the role of Ets-2, a transcription factor that is phosphorylated on a critical threonine residue (Thr-72) by the Ras/MAPK pathway in thymocyte development, has not been defined. Transgenic mice overexpressing a phosphomutant Ets-2 (T72A) in the thymus displayed reduced thymus size associated with a 60-80% reduction in thymocyte populations. The transgenic mice exhibited a 20-fold increase in a c-Kit(+) CD4(+) CD8(+) CD3(-) population and a 5-fold increase in a unique CD5(low) population associated with a partial developmental block at the DN2-DN3 stage of thymocytes. Transgenic thymocytes exhibited increased apoptosis, and overexpression of Bcl-2 rescued the hypocellularity and associated thymocyte developmental block in double transgenic mice. The observed defects in these mice are not dependent on Ets-1 expression. These studies implicate for the first time a stage-specific Ets-1-independent regulatory role for Ets-2 in early thymocyte development and survival.

Asunto(s)

Proteína Proto-Oncogénica c-ets-2/metabolismo , Treonina/metabolismo , Timocitos/citología , Timocitos/metabolismo , Sustitución de Aminoácidos , Animales , Apoptosis/genética , Recuento de Células , Proliferación Celular , Tamaño de la Célula , Supervivencia Celular/genética , Regulación de la Expresión Génica , Humanos , Ratones , Ratones Transgénicos , Mutación , Fosforilación , Multimerización de Proteína/genética , Estructura Cuaternaria de Proteína , Proteína Proto-Oncogénica c-ets-2/química , Proteína Proto-Oncogénica c-ets-2/genética , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Proteínas Proto-Oncogénicas c-kit/metabolismo , Proteínas ras/metabolismo