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

Research output: Contribution to journalArticle

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.

Details

Authors
  • Dung Fang Lee
  • Jie Su
  • Yen Sin Ang
  • Xonia Carvajal-Vergara
  • Sonia Mulero-Navarro
  • Julian Gingold
  • Hung Liang Wang
  • Ruiying Zhao
  • Ana Sevilla
  • Henia Darr
  • Andrew J K Williamson
  • Betty Chang
  • Xiaohong Niu
  • Francesca Aguilo
  • Elsa R. Flores
  • Yuh Pyng Sher
  • Mien Chie Hung
  • Anthony D. Whetton
  • Bruce D. Gelb
  • Kateri A. Moore
  • Hans Willem Snoeck
  • Avi Ma'Ayan
  • Christoph Schaniel
  • Ihor R. Lemischka
External organisations
  • Icahn School of Medicine at Mount Sinai
  • China Medical University Taichung
  • University of Texas
  • University of Manchester
  • University of Texas Graduate School of Biomedical Sciences at Houston
Original languageEnglish
Pages (from-to)179-194
Number of pages16
JournalCell Stem Cell
Volume11
Issue number2
Publication statusPublished - 2012 Aug 3
Publication categoryResearch
Peer-reviewedYes
Externally publishedYes