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Cell Stem Cell. 2015 Jan 8;16(1):39-50. doi: 10.1016/j.stem.2014.10.019. Epub 2014 Nov 13.

Inhibition of pluripotency networks by the Rb tumor suppressor restricts reprogramming and tumorigenesis.

Author information

1
Department of Pediatrics, Stanford University, Stanford, CA 94305, USA; Department of Genetics, Stanford University, Stanford, CA 94305, USA; Department of Pathology, Stanford University, Stanford, CA 94305, USA; Stanford Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, Stanford, CA 94305, USA.
2
Department of Pediatrics, Stanford University, Stanford, CA 94305, USA; Department of Genetics, Stanford University, Stanford, CA 94305, USA.
3
Department of Pathology, Stanford University, Stanford, CA 94305, USA; Stanford Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, Stanford, CA 94305, USA.
4
Department of Genetics, Stanford University, Stanford, CA 94305, USA; Paul F. Glenn Laboratories for the Biology of Aging, Stanford University, Stanford, CA 94305, USA.
5
London Regional Cancer Program, Children's Research Institute, Western University, London, ON N6A 4L6, Canada.
6
Department of Medicine, Stanford University, Stanford, CA 94305, USA; Department of Biochemistry, Stanford University, Stanford, CA 94305, USA; Stanford Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, Stanford, CA 94305, USA.
7
Department of Pediatrics, Stanford University, Stanford, CA 94305, USA; Department of Genetics, Stanford University, Stanford, CA 94305, USA. Electronic address: julsage@stanford.edu.
8
Department of Pathology, Stanford University, Stanford, CA 94305, USA; Stanford Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, Stanford, CA 94305, USA. Electronic address: wernig@stanford.edu.

Abstract

Mutations in the retinoblastoma tumor suppressor gene Rb are involved in many forms of human cancer. In this study, we investigated the early consequences of inactivating Rb in the context of cellular reprogramming. We found that Rb inactivation promotes the reprogramming of differentiated cells to a pluripotent state. Unexpectedly, this effect is cell cycle independent, and instead reflects direct binding of Rb to pluripotency genes, including Sox2 and Oct4, which leads to a repressed chromatin state. More broadly, this regulation of pluripotency networks and Sox2 in particular is critical for the initiation of tumors upon loss of Rb in mice. These studies therefore identify Rb as a global transcriptional repressor of pluripotency networks, providing a molecular basis for previous reports about its involvement in cell fate pliability, and implicate misregulation of pluripotency factors such as Sox2 in tumorigenesis related to loss of Rb function.

PMID:
25467916
PMCID:
PMC4389904
DOI:
10.1016/j.stem.2014.10.019
[Indexed for MEDLINE]
Free PMC Article

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