Title | Embryonic Stem Cell Growth Factors Regulate eIF2α Phosphorylation. |
Publication Type | Journal Article |
Year of Publication | 2015 |
Authors | Friend K, Brooks HA, Propson NE, Thomson JA, Kimble J |
Journal | PLoS One |
Volume | 10 |
Issue | 9 |
Pagination | e0139076 |
Date Published | 2015 |
ISSN | 1932-6203 |
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. |
DOI | 10.1371/journal.pone.0139076 |
Alternate Journal | PLoS ONE |
PubMed ID | 26406898 |
PubMed Central ID | PMC4583406 |
Grant List | 1U01 HL099773-01 / HL / NHLBI NIH HHS / United States GM069454 / GM / NIGMS NIH HHS / United States / / Howard Hughes Medical Institute / United States |