title: Upregulation of eIF5B controls cell-cycle arrest and specific developmental stages.
abstract: Proliferation arrest and distinct developmental stages alter and decrease general translation yet maintain ongoing translation. The factors that support translation in these conditions remain to be characterized. We investigated an altered translation factor in three cell states considered to have reduced general translation: immature Xenopus laevis oocytes, mouse ES cells, and the transition state of proliferating mammalian cells to quiescence (G0) upon growth-factor deprivation. Our data reveal a transient increase of eukaryotic translation initiation factor 5B (eIF5B), the eukaryotic ortholog of bacterial initiation factor IF2, in these conditions. eIF5B promotes 60S ribosome subunit joining and pre-40S subunit proofreading. eIF5B has also been shown to promote the translation of viral and stress-related mRNAs and can contribute indirectly to supporting or stabilizing initiator methionyl tRNA (tRNA-Met(i)) association with the ribosome. We find that eIF5B is a limiting factor for translation in these three conditions. The increased eIF5B levels lead to increased eIF5B complexes with tRNA-Met(i) upon serum starvation of THP1 mammalian cells. In addition, increased phosphorylation of eukaryotic initiation factor 2α, the translation factor that recruits initiator tRNA-Meti for general translation, is observed in these conditions. Importantly, we find that eIF5B is an antagonist of G0 and G0-like states, as eIF5B depletion reduces maturation of G0-like, immature oocytes and hastens early G0 arrest in serum-starved THP1 cells. Consistently, eIF5B overexpression promotes maturation of G0-like immature oocytes and causes cell death, an alternative to G0, in serum-starved THP1 cells. These data reveal a critical role for a translation factor that regulates specific cell-cycle transition and developmental stages.
authors.affiliation: Center for Cancer Research, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114.
authors.forename: Sooncheol
authors.initials: S
authors.lastname: Lee
authors.affiliation: Center for Cancer Research, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114.
authors.forename: Samuel S
authors.initials: SS
authors.lastname: Truesdell
authors.affiliation: Center for Cancer Research, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114.
authors.forename: Syed I A
authors.initials: SI
authors.lastname: Bukhari
authors.affiliation: Center for Cancer Research, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114.
authors.forename: Ju Huck
authors.initials: JH
authors.lastname: Lee
authors.affiliation: Center for Cancer Research, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114.
authors.forename: Olivier
authors.initials: O
authors.lastname: LeTonqueze
authors.affiliation: Center for Cancer Research, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114 vasudevan.shobha@mgh.harvard.edu.
authors.forename: Shobha
authors.initials: S
authors.lastname: Vasudevan
mesh_terms: D000818:Animals; D059447:Cell Cycle Checkpoints; D002460:Cell Line; D002470:Cell Survival; D016895:Culture Media, Serum-Free; D053595:Embryonic Stem Cells / Q000166:cytology / Q000378:metabolism; D015852:Eukaryotic Initiation Factor-2 / Q000378:metabolism; D039642:Eukaryotic Initiation Factors / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D051379:Mice; D009865:Oocytes / Q000166:cytology / Q000378:metabolism; D010766:Phosphorylation; D014176:Protein Biosynthesis; D012358:RNA, Transfer, Met; D015854:Up-Regulation; D014982:Xenopus laevis
chemical_list: D016895:Culture Media, Serum-Free; D015852:Eukaryotic Initiation Factor-2; D039642:Eukaryotic Initiation Factors; D012358:RNA, Transfer, Met; C451459:eukaryotic initiation factor-5B
keywords: eIF2α phosphorylation; early serum starvation; embryonic stem cells