Transcriptional regulation of Sox2 by the retinoblastoma family of pocket proteins
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Jéssica M. Vilas1,*, Alba Ferreirós1,*, Carmen Carneiro2, Lluis Morey3, Sabela Da Silva-Álvarez1, Tânia Fernandes2, María Abad4, Luciano Di Croce3,5, Tomás García-Caballero6, Manuel Serrano4, Carmen Rivas7,8, Anxo Vidal2 and Manuel Collado1
1 Instituto de Investigación Sanitaria de Santiago de Compostela (IDIS), Complexo Hospitalario Universitario de Santiago de Compostela (CHUS), SERGAS, E15706 Santiago de Compostela, Spain
2 Departamento de Fisioloxía and Centro de Investigación en Medicina Molecular (CIMUS), Universidade de Santiago de Compostela, Instituto de Investigaciones Sanitarias de Santiago de Compostela (IDIS), E15782 Santiago de Compostela, Spain
3 Centre for Genomic Regulation and UPF, E08003 Barcelona, Spain
4 Tumor Suppression Group, Spanish National Cancer Research Centre (CNIO), E28029 Madrid, Spain
5 Institució Catalana de Recerca i Estudis Avançats (ICREA), E08010 Barcelona, Spain
6 Departamento de Ciencias Morfológicas, Facultad de Medicina. USC. Complejo Hospitalario de Santiago (CHUS), SERGAS, E15706, Santiago de Compostela, Spain
7 Departamento de Biología Molecular y Celular, Centro Nacional de Biotecnología-CSIC, E28049 Madrid, Spain
8 Centro de Investigación en Medicina Molecular (CIMUS), Universidade de Santiago de Compostela, Instituto de Investigaciones Sanitarias de Santiago de Compostela (IDIS), E15706 Santiago de Compostela, Spain
* These authors contributed equally and should be considered co-first authors
Manuel Collado, email:
Anxo Vidal, email:
Keywords: retinoblastoma, Sox2, stem cells, cancer
Received: November 28, 2014 Accepted: December 14, 2014 Published: December 18, 2014
Cellular reprogramming to iPSCs has uncovered unsuspected links between tumor suppressors and pluripotency factors. Using this system, it was possible to identify tumor suppressor p27 as a repressor of Sox2 during differentiation. This led to the demonstration that defects in the repression of Sox2 can contribute to tumor development. The members of the retinoblastoma family of pocket proteins, pRb, p107 and p130, are negative regulators of the cell cycle with tumor suppressor activity and with roles in differentiation. In this work we studied the relative contribution of the retinoblastoma family members to the regulation of Sox2 expression. We found that deletion of Rb or p130 leads to impaired repression of Sox2, a deffect amplified by inactivation of p53. We also identified binding of pRb and p130 to an enhancer with crucial regulatory activity on Sox2 expression. Using cellular reprogramming we tested the impact of the defective repression of Sox2 and confirmed that Rb deficiency allows the generation of iPSCs in the absence of exogenous Sox2. Finally, partial depletion of Sox2 positive cells reduced the pituitary tumor development initiated by Rb loss in vivo. In summary, our results show that Sox2 repression by pRb is a relevant mechanism of tumor suppression.
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