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

Michael S. Kareta, Laura L. Gorges, Sana Hafeez, Bérénice A. Benayoun, Samuele Marro, Anne Flore Zmoos, Matthew J. Cecchini, Damek Spacek, Luis F.Z. Batista, Megan O'Brien, Yi Han Ng, Cheen Euong Ang, Dedeepya Vaka, Steven E. Artandi, Frederick A. Dick, Anne Brunet, Julien Sage, Marius Wernig

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Pages (from-to)39-50
Number of pages12
JournalCell Stem Cell
Volume16
Issue number1
DOIs
StatePublished - Jan 8 2015

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Carcinogenesis
Retinoblastoma
Tumor Suppressor Genes
Pliability
Chromatin
Neoplasms
Cell Cycle
Mutation
Genes
Cellular Reprogramming

ASJC Scopus subject areas

  • Molecular Medicine
  • Genetics
  • Cell Biology

Cite this

Inhibition of pluripotency networks by the Rb tumor suppressor restricts reprogramming and tumorigenesis. / Kareta, Michael S.; Gorges, Laura L.; Hafeez, Sana; Benayoun, Bérénice A.; Marro, Samuele; Zmoos, Anne Flore; Cecchini, Matthew J.; Spacek, Damek; Batista, Luis F.Z.; O'Brien, Megan; Ng, Yi Han; Ang, Cheen Euong; Vaka, Dedeepya; Artandi, Steven E.; Dick, Frederick A.; Brunet, Anne; Sage, Julien; Wernig, Marius.

In: Cell Stem Cell, Vol. 16, No. 1, 08.01.2015, p. 39-50.

Research output: Contribution to journalArticle

Kareta, MS, Gorges, LL, Hafeez, S, Benayoun, BA, Marro, S, Zmoos, AF, Cecchini, MJ, Spacek, D, Batista, LFZ, O'Brien, M, Ng, YH, Ang, CE, Vaka, D, Artandi, SE, Dick, FA, Brunet, A, Sage, J & Wernig, M 2015, 'Inhibition of pluripotency networks by the Rb tumor suppressor restricts reprogramming and tumorigenesis', Cell Stem Cell, vol. 16, no. 1, pp. 39-50. https://doi.org/10.1016/j.stem.2014.10.019
Kareta, Michael S. ; Gorges, Laura L. ; Hafeez, Sana ; Benayoun, Bérénice A. ; Marro, Samuele ; Zmoos, Anne Flore ; Cecchini, Matthew J. ; Spacek, Damek ; Batista, Luis F.Z. ; O'Brien, Megan ; Ng, Yi Han ; Ang, Cheen Euong ; Vaka, Dedeepya ; Artandi, Steven E. ; Dick, Frederick A. ; Brunet, Anne ; Sage, Julien ; Wernig, Marius. / Inhibition of pluripotency networks by the Rb tumor suppressor restricts reprogramming and tumorigenesis. In: Cell Stem Cell. 2015 ; Vol. 16, No. 1. pp. 39-50.
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