Embryonic Stem Cell Growth Factors Regulate eIF2 alpha Phosphorylation

作者：Friend Kyle^*; Brooks Hunter A; Propson Nicholas E; Thomson James A; Kimble Judith

来源：PLos One, 2015, 10(9): e0139076.

DOI：10.1371/journal.pone.0139076

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 eIF2 alpha-mediated translational control (eIF2 alpha phosphorylation promotes protein expression from mRNAs with upstream open-reading frames, or uORFs). We find abundant phosphorylated P-eIF2 alpha (P-eIF2 alpha) in both pluripotent mouse and human ESCs, but little P-eIF2 alpha in ESCs triggered to differentiate. We show that the growth factors LIF (leukemia inhibitory factor) and BMP4 (bone morphogenic protein 4) both maintain P-eIF2 alpha in mESCs, but use distinct mechanisms: LIF inhibits an eIF2 alpha phosphatase whereas BMP4 activates an eIF2 alpha 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 eIF2 alpha phosphorylation, promotes Nanog and c-Myc expression, but not Oct4 expression. These experiments connect ESC growth factors to eIF2 alpha phosphorylation and suggest a chemical substitute for LIF to enhance Nanog and c-Myc expression.

• 出版日期2015-9-25