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An unexpected tumor suppresor role for the Rac1 exchange factor Vav1 in T cell acute lymphoblastic leukemia

AuthorsRobles-Valero, Javier ; Lorenzo-Martín, L. Francisco; Menacho-Márquez, Mauricio ; Abad, Antonio; Espinosa, Lluis; Bigas, Anna; Bustelo, Xosé R.
Issue Date2016
PublisherSociedad Española de Bioquímica y Biología Molecular
CitationXXXIX Congreso de la SEBBM (2016)
AbstractGTPases, are widely deemed as potential therapeutic targets owing to their protumorigenic functions. However, the sparse use of animal models has precluded the full understanding of their in vivo pathophysiological roles. Here, we report that the hematopoietic-specific Vav1 GEF unexpectedly acts as a tumor suppressor by buffering Notch1 signaling in lymphocytes. This noncanonical function entails the nucleation of cytoplasmic complexes between Cbl-b and the active Notch1 intracellular domain (ICN1) that favor the ubiquitinylation-mediated degradation of ICN1. Genetic ablation of Vav1 upregulates ICN1 signaling in immature T cells and, in collaboration with ancillary mutations, triggers the rapid development of T cell acute lymphoblastic leukemia (T-ALL). This pathway is downregulated at the transcriptional level in human T-ALL of the TLX+ subtype, further underscoring its potential tumor suppressing roles. These results call for an overall reevaluation of Rho GEF function in cancer.
DescriptionResumen del póster presentado al XXXIX Congreso de la Sociedad Española de Bioquímica y Biología Molecular, celebrado en Salamanca del 5 al 8 de septiembre de 2016.
Appears in Collections:(IBMCC) Comunicaciones congresos
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