Browsing by Keyword "Ras signaling"
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Publication Inactivation of Capicua in adult mice causes T-cell lymphoblastic lymphoma(Cold Spring Harbor Laboratory Press, 2017-07-15) Simón-Carrasco, Lucía; Graña Castro, Osvaldo; Salmón, Marina; Jacob, Harrys K C; Gutierrez, Alejandro; Jiménez, Gerardo; Drosten, Matthias; Barbacid, Mariano; Fundación La Marató TV3; Unión Europea. Comisión Europea. European Research Council (ERC); Ministerio de Economía y Competitividad (España); Comunidad de Madrid (España); Asociación Española Contra el Cáncer; Fundación AXACIC (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.Publication The Capicua tumor suppressor: a gatekeeper of Ras signaling in development and cancer(Taylor & Francis, 2018-06-17) Simón-Carrasco, Lucía; Jiménez, Gerardo; Barbacid, Mariano; Drosten, Matthias; Fundación La Marató TV3; Unión Europea. Comisión Europea. European Research Council (ERC); Comunidad de Madrid (España); Asociación Española Contra el Cáncer; Fundación AXA; Ministerio de Economía y Competitividad (España)The transcriptional repressor Capicua (CIC) has emerged as an important rheostat of cell growth regulated by RAS/MAPK signaling. Cic was originally discovered in Drosophila, where it was shown to be inactivated by MAPK signaling downstream of the RTKs Torso and EGFR, which results in signal-dependent responses that are required for normal cell fate specification, proliferation and survival of developing and adult tissues. CIC is highly conserved in mammals, where it is also negatively regulated by MAPK signaling. Here, we review the roles of CIC during mammalian development, tissue homeostasis, tumor formation and therapy resistance. Available data indicate that CIC is involved in multiple biological processes, including lung development, liver homeostasis, autoimmunity and neurobehavioral processes. Moreover, CIC has been shown to be involved in tumor development as a tumor suppressor, both in human as well as in mouse models. Finally, several lines of evidence implicate CIC as a determinant of sensitivity to EGFR and MAPK pathway inhibitors, suggesting that CIC may play a broader role in human cancer than originally anticipated.