Por favor, use este identificador para citar o enlazar este Item:http://hdl.handle.net/20.500.12105/8392
Título
Inactivation of Capicua in adult mice causes T-cell lymphoblastic lymphoma
Autor(es)
Simón-Carrasco, Lucía | Graña Castro, Osvaldo CNIO | Salmón, Marina | Jacob, Harrys K C | Gutierrez, Alejandro | Jiménez, Gerardo | Drosten, Matthias CNIO | Barbacid, Mariano CNIO
Fecha de publicación
2017-07-15
Cita
Genes Dev. 2017 ;31(14):1456-1468.
Idioma
Inglés
Tipo de documento
journal article
Resumen
CIC (also known as Capicua) is a transcriptional repressor negatively regulated by RAS/MAPK signaling. Whereas the functions of Cic have been well characterized in Drosophila, little is known about its role in mammals. CIC is inactivated in a variety of human tumors and has been implicated recently in the promotion of lung metastases. Here, we describe a mouse model in which we inactivated Cic by selectively disabling its DNA-binding activity, a mutation that causes derepression of its target genes. Germline Cic inactivation causes perinatal lethality due to lung differentiation defects. However, its systemic inactivation in adult mice induces T-cell acute lymphoblastic lymphoma (T-ALL), a tumor type known to carry CIC mutations, albeit with low incidence. Cic inactivation in mice induces T-ALL by a mechanism involving derepression of its well-known target, Etv4 Importantly, human T-ALL also relies on ETV4 expression for maintaining its oncogenic phenotype. Moreover, Cic inactivation renders T-ALL insensitive to MEK inhibitors in both mouse and human cell lines. Finally, we show that Ras-induced mouse T-ALL as well as human T-ALL carrying mutations in the RAS/MAPK pathway display a genetic signature indicative of Cic inactivation. These observations illustrate that CIC inactivation plays a key role in this human malignancy.
Palabras clave
MESH
Adenovirus E1A Proteins | Alleles | Animals | Brain Neoplasms | Cell Line, Tumor | Embryonic Development | Fibroblasts | Genes, ras | Humans | MAP Kinase Signaling System | Mice | Mutation | Oligodendroglioma | Precursor T-Cell Lymphoblastic Leukemia-Lymphoma | Proto-Oncogene Proteins | Proto-Oncogene Proteins c-ets | Repressor Proteins | Transcription, Genetic
Versión en línea
DOI
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