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Embryonic Stem Cell Growth Factors Regulate eIF2α Phosphorylation.

Kyle Friend1, Hunter A Brooks2, Nicholas E Propson3

  • 1Department of Biochemistry, University of Wisconsin-Madison, Madison, Wisconsin, 53706, United States of America; Department of Chemistry and Biochemistry, Washington and Lee University, Lexington, Virginia, 24450, United States of America.

Plos One
|September 26, 2015
PubMed
Summary
This summary is machine-generated.

Embryonic stem cells (ESCs) use phosphorylated eIF2α for pluripotency. Growth factors like LIF and BMP4 regulate this, with salubrinal potentially replacing LIF to boost Nanog and c-Myc expression.

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Area of Science:

  • Stem cell biology
  • Molecular and Cell Biology
  • Translational regulation

Background:

  • Pluripotent stem cells (ESCs) are regulated by growth and transcription factors.
  • Translational control mechanisms in ESCs are less understood.
  • eIF2α phosphorylation regulates protein expression from mRNAs with upstream open-reading frames (uORFs).

Purpose of the Study:

  • Investigate the link between ESC growth factors and eIF2α-mediated translational control.
  • Determine the role of phosphorylated eIF2α (P-eIF2α) in maintaining pluripotency.
  • Identify mechanisms by which growth factors regulate P-eIF2α levels.

Main Methods:

  • Quantification of P-eIF2α in mouse and human ESCs during pluripotency and differentiation.
  • Assessing the effects of leukemia inhibitory factor (LIF) and bone morphogenic protein 4 (BMP4) on P-eIF2α levels.
  • Utilizing salubrinal, a chemical inducer of eIF2α phosphorylation, to study its impact on pluripotency gene expression.

Main Results:

  • Abundant P-eIF2α was found in pluripotent ESCs, decreasing upon differentiation.
  • LIF and BMP4 maintain P-eIF2α in mouse ESCs via distinct pathways (phosphatase inhibition and kinase activation, respectively).
  • Salubrinal treatment increased Nanog and c-Myc expression, which have uORFs, but not Oct4 expression, which lacks uORFs.

Conclusions:

  • ESC growth factors are connected to eIF2α phosphorylation.
  • P-eIF2α plays a role in regulating the expression of key pluripotency factors like Nanog and c-Myc.
  • Salubrinal represents a potential chemical substitute for LIF to enhance Nanog and c-Myc expression in ESCs.