2026-07-21T16:29:07Zhttps://repisalud.isciii.es/rest/oai/requestoai:repisalud.isciii.es:20.500.12105/83922024-11-29T17:37:58Zcom_20.500.12105_2173com_20.500.12105_2051col_20.500.12105_19597
Repisalud
author
Simón-Carrasco, Lucía
author
Graña Castro, Osvaldo
author
Salmón, Marina
author
Jacob, Harrys K C
author
Gutierrez, Alejandro
author
Jiménez, Gerardo
author
Drosten, Matthias
author
Barbacid, Mariano
funder
Fundación La Marató TV3
funder
Unión Europea. Comisión Europea. European Research Council (ERC)
funder
Ministerio de Economía y Competitividad (España)
funder
Comunidad de Madrid (España)
funder
Asociación Española Contra el Cáncer
funder
Fundación AXA
2019-10-01T10:52:20Z
2019-10-01T10:52:20Z
2017-07-15
Genes Dev. 2017 ;31(14):1456-1468.
10.1101/gad.300244.117
1549-5477
0890-9369
Genes & development
28827401
http://hdl.handle.net/20.500.12105/8392
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.
eng
CIC
Etv4
Ras signaling
T-ALL
Mouse models
Inactivation of Capicua in adult mice causes T-cell lymphoblastic lymphoma
journal article
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