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Transcriptional regulation of Sox2 by the retinoblastoma family of pocket proteins.
- Source :
-
Oncotarget [Oncotarget] 2015 Feb 20; Vol. 6 (5), pp. 2992-3002. - Publication Year :
- 2015
-
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.
- Subjects :
- Animals
Cellular Reprogramming
Epigenesis, Genetic
Gene Expression Regulation, Developmental
Gene Expression Regulation, Neoplastic
Genotype
HEK293 Cells
Humans
Mice, 129 Strain
Mice, Inbred C57BL
Mice, Knockout
Neoplastic Stem Cells metabolism
Phenotype
Pituitary Neoplasms genetics
Pituitary Neoplasms metabolism
RNA Interference
Retinoblastoma Protein deficiency
Retinoblastoma Protein genetics
Retinoblastoma-Like Protein p107 genetics
Retinoblastoma-Like Protein p107 metabolism
Retinoblastoma-Like Protein p130 deficiency
Retinoblastoma-Like Protein p130 genetics
SOXB1 Transcription Factors deficiency
SOXB1 Transcription Factors genetics
Transfection
Tumor Suppressor Protein p53 genetics
Tumor Suppressor Protein p53 metabolism
Induced Pluripotent Stem Cells metabolism
Retinoblastoma Protein metabolism
Retinoblastoma-Like Protein p130 metabolism
SOXB1 Transcription Factors metabolism
Transcription, Genetic
Subjects
Details
- Language :
- English
- ISSN :
- 1949-2553
- Volume :
- 6
- Issue :
- 5
- Database :
- MEDLINE
- Journal :
- Oncotarget
- Publication Type :
- Academic Journal
- Accession number :
- 25576924
- Full Text :
- https://doi.org/10.18632/oncotarget.2996