Embryonic Stem Cell Growth Factors Regulate eIF2α Phosphorylation.

TitleEmbryonic Stem Cell Growth Factors Regulate eIF2α Phosphorylation.
Publication TypeJournal Article
Year of Publication2015
AuthorsFriend K, Brooks HA, Propson NE, Thomson JA, Kimble J
JournalPLoS One
Volume10
Issue9
Paginatione0139076
Date Published2015
ISSN1932-6203
Abstract

Growth factors and transcription factors are well known to regulate pluripotent stem cells, but less is known about translational control in stem cells. Here, we use embryonic stem cells (ESCs) to investigate a connection between ESC growth factors and eIF2α-mediated translational control (eIF2α phosphorylation promotes protein expression from mRNAs with upstream open-reading frames, or uORFs). We find abundant phosphorylated P-eIF2α (P-eIF2α) in both pluripotent mouse and human ESCs, but little P-eIF2α in ESCs triggered to differentiate. We show that the growth factors LIF (leukemia inhibitory factor) and BMP4 (bone morphogenic protein 4) both maintain P-eIF2α in mESCs, but use distinct mechanisms: LIF inhibits an eIF2α phosphatase whereas BMP4 activates an eIF2α kinase. The mRNAs encoding the pluripotency factors Nanog and c-Myc possess uORFs while Oct4 mRNA does not. We find that salubrinal, a chemical that increases eIF2α phosphorylation, promotes Nanog and c-Myc expression, but not Oct4 expression. These experiments connect ESC growth factors to eIF2α phosphorylation and suggest a chemical substitute for LIF to enhance Nanog and c-Myc expression.

DOI10.1371/journal.pone.0139076
Alternate JournalPLoS ONE
PubMed ID26406898
PubMed Central IDPMC4583406
Grant List1U01 HL099773-01 / HL / NHLBI NIH HHS / United States
GM069454 / GM / NIGMS NIH HHS / United States
/ / Howard Hughes Medical Institute / United States