Regulation of embryonic and induced pluripotency by aurora kinase-p53 signaling

Cell Stem Cell. 2012 Aug 3;11(2):179-94. doi: 10.1016/j.stem.2012.05.020.

Abstract

Many signals must be integrated to maintain self-renewal and pluripotency in embryonic stem cells (ESCs) and to enable induced pluripotent stem cell (iPSC) reprogramming. However, the exact molecular regulatory mechanisms remain elusive. To unravel the essential internal and external signals required for sustaining the ESC state, we conducted a short hairpin (sh) RNA screen of 104 ESC-associated phosphoregulators. Depletion of one such molecule, aurora kinase A (Aurka), resulted in compromised self-renewal and consequent differentiation. By integrating global gene expression and computational analyses, we discovered that loss of Aurka leads to upregulated p53 activity that triggers ESC differentiation. Specifically, Aurka regulates pluripotency through phosphorylation-mediated inhibition of p53-directed ectodermal and mesodermal gene expression. Phosphorylation of p53 not only impairs p53-induced ESC differentiation but also p53-mediated suppression of iPSC reprogramming. Our studies demonstrate an essential role for Aurka-p53 signaling in the regulation of self-renewal, differentiation, and somatic cell reprogramming.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Aurora Kinase A
  • Aurora Kinases
  • Cell Differentiation
  • Cell Line
  • Cell Proliferation
  • Embryonic Stem Cells / cytology
  • Embryonic Stem Cells / metabolism*
  • HEK293 Cells
  • Humans
  • Mice
  • Mice, Knockout
  • Phosphorylation
  • Pluripotent Stem Cells / cytology
  • Pluripotent Stem Cells / metabolism*
  • Protein-Serine-Threonine Kinases / antagonists & inhibitors
  • Protein-Serine-Threonine Kinases / metabolism*
  • Signal Transduction*
  • Tumor Suppressor Protein p53 / deficiency
  • Tumor Suppressor Protein p53 / genetics
  • Tumor Suppressor Protein p53 / metabolism*
  • Xenopus

Substances

  • Tumor Suppressor Protein p53
  • AURKA protein, human
  • Aurka protein, mouse
  • Aurora Kinase A
  • Aurora Kinases
  • Protein-Serine-Threonine Kinases

Associated data

  • GEO/GSE23541