The Capicua tumor suppressor: a gatekeeper of Ras signaling in development and cancer

Cell Cycle. 2018;17(6):702-711. doi: 10.1080/15384101.2018.1450029.

Abstract

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.

Keywords: CIC; Etv4; Ras signaling; T-ALL; mouse models.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Animals
  • Drosophila / growth & development
  • Drosophila / metabolism
  • Drug Resistance, Neoplasm / genetics
  • Gene Expression Regulation, Developmental
  • Humans
  • Neoplasms / genetics
  • Neoplasms / pathology
  • Protein Isoforms / genetics
  • Protein Isoforms / metabolism
  • Repressor Proteins / genetics
  • Repressor Proteins / metabolism*
  • Signal Transduction*
  • ras Proteins / metabolism*

Substances

  • Protein Isoforms
  • Repressor Proteins
  • ras Proteins

Grants and funding

This work has been supported by grants from the Fundació La Marató de TV3 (20131730/1) to G.J. and M.B., from the European Research Council (ERC-AG/250297-RAS AHEAD and ERC-AG/695566-THERACAN), the Autonomous Community of Madrid (S2011/BDM-2470/ONCOCYCLE) and the Foundation of the Asociación Española contra el Cáncer (AECC) (GC16173694BARB) to M.B, and the Spanish Ministry of Economy and Competitiveness (SAF2014-59864-R to M.B. and BFU2014-52863-P to G.J.). M.B. is the recipient of an Endowed Chair from the AXA Research Fund. L.S.C. has been supported by a fellowship from the Programa de Formación de Personal Investigator (FPI) of the Spanish Ministry of Economy and Competitiveness.