title: Multifaceted regulation of somatic cell reprogramming by mRNA translational control.
abstract: Translational control plays a pivotal role in the regulation of the pluripotency network in embryonic stem cells, but its effect on reprogramming somatic cells to pluripotency has not been explored. Here, we show that eukaryotic translation initiation factor 4E (eIF4E) binding proteins (4E-BPs), which are translational repressors, have a multifaceted effect on the reprogramming of mouse embryonic fibroblasts (MEFs) into induced pluripotent stem cells (iPSCs). Loss of 4E-BP expression attenuates the induction of iPSCs at least in part through increased translation of p21, a known inhibitor of somatic cell reprogramming. However, MEFs lacking both p53 and 4E-BPs show greatly enhanced reprogramming resulting from a combination of reduced p21 transcription and enhanced translation of endogenous mRNAs such as Sox2 and Myc and can be reprogrammed through the expression of only exogenous Oct4. Thus, 4E-BPs exert both positive and negative effects on reprogramming, highlighting the key role that translational control plays in regulating this process.
authors.affiliation: The Rosalind and Morris Goodman Cancer Research Center, McGill University, Montréal, QC H3A 1A3, Canada; Department of Biochemistry, McGill University, Montréal, QC H3A 1A3, Canada.
authors.forename: Soroush
authors.initials: S
authors.lastname: Tahmasebi
authors.affiliation: Children's Hospital of Eastern Ontario Research Institute and Department of Biochemistry, Microbiology, and Immunology, University of Ottawa, Ottawa, ON K1H 8L1, Canada.
authors.forename: Tommy
authors.initials: T
authors.lastname: Alain
authors.affiliation: Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Vinagolu K
authors.initials: VK
authors.lastname: Rajasekhar
authors.affiliation: The Rosalind and Morris Goodman Cancer Research Center, McGill University, Montréal, QC H3A 1A3, Canada; Department of Medicine, McGill University Health Center, Montréal, QC H3A 1A3, Canada.
authors.forename: Jiang-Ping
authors.initials: JP
authors.lastname: Zhang
authors.affiliation: Centre for Research in Neuroscience, Research Institute of the McGill University Health Centre, Montréal General Hospital, Montréal, QC H3G 1A4, Canada.
authors.forename: Masha
authors.initials: M
authors.lastname: Prager-Khoutorsky
authors.affiliation: The Rosalind and Morris Goodman Cancer Research Center, McGill University, Montréal, QC H3A 1A3, Canada; Department of Biochemistry, McGill University, Montréal, QC H3A 1A3, Canada.
authors.forename: Arkady
authors.initials: A
authors.lastname: Khoutorsky
authors.affiliation: Cancer Biology and Genetics, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Yildirim
authors.initials: Y
authors.lastname: Dogan
authors.affiliation: Patrick Wild Centre, Centre for Integrative Physiology, University of Edinburgh, Edinburgh EH8 9XD, UK.
authors.forename: Christos G
authors.initials: CG
authors.lastname: Gkogkas
authors.affiliation: The Rosalind and Morris Goodman Cancer Research Center, McGill University, Montréal, QC H3A 1A3, Canada; Department of Biochemistry, McGill University, Montréal, QC H3A 1A3, Canada.
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Petroulakis
authors.affiliation: The Rosalind and Morris Goodman Cancer Research Center, McGill University, Montréal, QC H3A 1A3, Canada; Department of Biochemistry, McGill University, Montréal, QC H3A 1A3, Canada.
authors.forename: Annie
authors.initials: A
authors.lastname: Sylvestre
authors.affiliation: The Rosalind and Morris Goodman Cancer Research Center, McGill University, Montréal, QC H3A 1A3, Canada; Department of Medicine, McGill University Health Center, Montréal, QC H3A 1A3, Canada.
authors.forename: Mohammad
authors.initials: M
authors.lastname: Ghorbani
authors.affiliation: The Rosalind and Morris Goodman Cancer Research Center, McGill University, Montréal, QC H3A 1A3, Canada; Department of Biochemistry, McGill University, Montréal, QC H3A 1A3, Canada.
authors.forename: Sarah
authors.initials: S
authors.lastname: Assadian
authors.affiliation: The Rosalind and Morris Goodman Cancer Research Center, McGill University, Montréal, QC H3A 1A3, Canada; Department of Human Genetics, McGill University, Montréal, QC H3A 1A3, Canada.
authors.forename: Yojiro
authors.initials: Y
authors.lastname: Yamanaka
authors.affiliation: Cancer Biology and Genetics, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Julia R
authors.initials: JR
authors.lastname: Vinagolu-Baur
authors.affiliation: The Rosalind and Morris Goodman Cancer Research Center, McGill University, Montréal, QC H3A 1A3, Canada; Department of Biochemistry, McGill University, Montréal, QC H3A 1A3, Canada.
authors.forename: Jose G
authors.initials: JG
authors.lastname: Teodoro
authors.affiliation: Cancer Biology and Genetics, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Kitai
authors.initials: K
authors.lastname: Kim
authors.affiliation: The Rosalind and Morris Goodman Cancer Research Center, McGill University, Montréal, QC H3A 1A3, Canada; Department of Biochemistry, McGill University, Montréal, QC H3A 1A3, Canada; Department of Medicine, McGill University Health Center, Montréal, QC H3A 1A3, Canada. Electronic address: xiang-jiao.yang@mcgill.ca.
authors.forename: Xiang-Jiao
authors.initials: XJ
authors.lastname: Yang
authors.affiliation: The Rosalind and Morris Goodman Cancer Research Center, McGill University, Montréal, QC H3A 1A3, Canada; Department of Biochemistry, McGill University, Montréal, QC H3A 1A3, Canada; Department of Medicine, McGill University Health Center, Montréal, QC H3A 1A3, Canada. Electronic address: nahum.sonenberg@mcgill.ca.
authors.forename: Nahum
authors.initials: N
authors.lastname: Sonenberg
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D018797:Cell Cycle Proteins; D002478:Cells, Cultured; D065150:Cellular Reprogramming / Q000235:genetics / Q000502:physiology*; D053595:Embryonic Stem Cells / Q000166:cytology / Q000378:metabolism; D039642:Eukaryotic Initiation Factors / Q000235:genetics / Q000378:metabolism; D057026:Induced Pluripotent Stem Cells / Q000166:cytology / Q000378:metabolism; D051379:Mice; D008954:Models, Biological; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism; D055748:SOXB1 Transcription Factors / Q000235:genetics / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; C499527:Eif4ebp1 protein, mouse; C491255:Eif4ebp2 protein, mouse; D039642:Eukaryotic Initiation Factors; C489428:Myc protein, mouse; D010750:Phosphoproteins; D016271:Proto-Oncogene Proteins c-myc; D055748:SOXB1 Transcription Factors