title: Transcriptional regulation of Sox2 by the retinoblastoma family of pocket proteins.
abstract: 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.
authors.affiliation: Instituto de Investigación Sanitaria de Santiago de Compostela (IDIS), Complexo Hospitalario Universitario de Santiago de Compostela (CHUS), SERGAS, E15706 Santiago de Compostela, Spain.
authors.forename: Jéssica M
authors.initials: JM
authors.lastname: Vilas
authors.affiliation: Instituto de Investigación Sanitaria de Santiago de Compostela (IDIS), Complexo Hospitalario Universitario de Santiago de Compostela (CHUS), SERGAS, E15706 Santiago de Compostela, Spain.
authors.forename: Alba
authors.initials: A
authors.lastname: Ferreirós
authors.affiliation: 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.
authors.forename: Carmen
authors.initials: C
authors.lastname: Carneiro
authors.affiliation: Centre for Genomic Regulation and UPF, E08003 Barcelona, Spain.
authors.forename: Lluis
authors.initials: L
authors.lastname: Morey
authors.affiliation: Instituto de Investigación Sanitaria de Santiago de Compostela (IDIS), Complexo Hospitalario Universitario de Santiago de Compostela (CHUS), SERGAS, E15706 Santiago de Compostela, Spain.
authors.forename: Sabela
authors.initials: S
authors.lastname: Da Silva-Álvarez
authors.affiliation: 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.
authors.forename: Tânia
authors.initials: T
authors.lastname: Fernandes
authors.affiliation: Tumor Suppression Group, Spanish National Cancer Research Centre (CNIO), E28029 Madrid, Spain.
authors.forename: María
authors.initials: M
authors.lastname: Abad
authors.affiliation: Centre for Genomic Regulation and UPF, E08003 Barcelona, Spain.|Institució Catalana de Recerca i Estudis Avançats (ICREA), E08010 Barcelona, Spain.
authors.forename: Luciano
authors.initials: L
authors.lastname: Di Croce
authors.affiliation: Departamento de Ciencias Morfológicas, Facultad de Medicina. USC. Complejo Hospitalario de Santiago (CHUS), SERGAS, E15706, Santiago de Compostela, Spain.
authors.forename: Tomás
authors.initials: T
authors.lastname: García-Caballero
authors.affiliation: Tumor Suppression Group, Spanish National Cancer Research Centre (CNIO), E28029 Madrid, Spain.
authors.forename: Manuel
authors.initials: M
authors.lastname: Serrano
authors.affiliation: Departamento de Biología Molecular y Celular, Centro Nacional de Biotecnología-CSIC, E28049 Madrid, Spain.|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.
authors.forename: Carmen
authors.initials: C
authors.lastname: Rivas
authors.affiliation: 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.
authors.forename: Anxo
authors.initials: A
authors.lastname: Vidal
authors.affiliation: Instituto de Investigación Sanitaria de Santiago de Compostela (IDIS), Complexo Hospitalario Universitario de Santiago de Compostela (CHUS), SERGAS, E15706 Santiago de Compostela, Spain.
authors.forename: Manuel
authors.initials: M
authors.lastname: Collado
mesh_terms: D000818:Animals; D065150:Cellular Reprogramming; D044127:Epigenesis, Genetic; D018507:Gene Expression Regulation, Developmental; D015972:Gene Expression Regulation, Neoplastic; D005838:Genotype; D057809:HEK293 Cells; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000378:metabolism*; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D014411:Neoplastic Stem Cells / Q000378:metabolism; D010641:Phenotype; D010911:Pituitary Neoplasms / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D016160:Retinoblastoma Protein / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D050720:Retinoblastoma-Like Protein p107 / Q000235:genetics / Q000378:metabolism; D050717:Retinoblastoma-Like Protein p130 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D055748:SOXB1 Transcription Factors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic; D014162:Transfection; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism
chemical_list: C489485:Rbl1 protein, mouse; C493838:Rbl2 protein, mouse; D016160:Retinoblastoma Protein; D050720:Retinoblastoma-Like Protein p107; D050717:Retinoblastoma-Like Protein p130; D055748:SOXB1 Transcription Factors; C527783:Sox2 protein, mouse; D016159:Tumor Suppressor Protein p53