Rem2 GTPase maintains survival of human embryonic stem cells as well as enhancing reprogramming by regulating p53 and cyclin D1

Michael J. Edel, Cristina Menchon, Sergio Menendez, Antonella Consiglio, Angel Raya, Juan Carlos Izpisua Belmonte

Research output: Contribution to journalArticlepeer-review

67 Scopus citations

Abstract

Human pluripotent stem cells, such as embryonic stem cells (hESCs) and induced pluripotent stem cells (iPSCs), have the unique abilities of differentiation into any cell type of the organism (pluripotency) and indefinite selfrenewal. Here, we show that the Rem2 GTPase, a suppressor of the p53 pathway, is up-regulated in hESCs and, by loss- and gain-of-function studies, that it is a major player in the maintenance of hESC self-renewal and pluripotency. We show that Rem2 mediates the fibroblastic growth factor 2 (FGF2) signaling pathway to maintain proliferation of hESCs. We demonstrate that Rem2 effects are mediated by suppressing the transcriptional activity of p53 and cyclin D1 to maintain survival of hESCs. Importantly, Rem2 does this by preventing protein degradation during DNA damage. Given that Rem2 maintains hESCs, we also show that it is as efficient as c-Myc by enhancing reprogramming of human somatic cells into iPSCs eightfold. Rem2 does this by accelerating the cell cycle and protecting from apoptosis via its effects on cyclin D1 expression/localization and suppression of p53 transcription. We show that the effects of Rem2 on cyclin D1 are independent of p53 function. These results define the cell cycle and apoptosis as a rate-limiting step during the reprogramming phenomena. Our studies highlight the possibility of reprogramming somatic cells by imposing hESC-specific cell cycle features for making safer iPSCs for cell therapy use.

Original languageEnglish (US)
Pages (from-to)561-573
Number of pages13
JournalGenes and Development
Volume24
Issue number6
DOIs
StatePublished - Mar 15 2010

Keywords

  • Cyclin D1
  • Rem2
  • Reprogramming
  • Self-renewal
  • p53

ASJC Scopus subject areas

  • Genetics
  • Developmental Biology

Fingerprint Dive into the research topics of 'Rem2 GTPase maintains survival of human embryonic stem cells as well as enhancing reprogramming by regulating p53 and cyclin D1'. Together they form a unique fingerprint.

Cite this