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

Lee, Dung Fang; Su, Jie; Ang, Yen Sin; Carvajal-Vergara, Xonia; Mulero-Navarro, Sonia; Pereira, Carlos F. LU ; Gingold, Julian; Wang, Hung Liang; Zhao, Ruiying and Sevilla, Ana, et al. (2012) In Cell Stem Cell 11(2). p.179-194
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... (More)

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.

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published
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Cell Stem Cell
volume
11
issue
2
pages
16 pages
publisher
Cell Press
external identifiers
  • scopus:84864631288
ISSN
1934-5909
DOI
10.1016/j.stem.2012.05.020
language
English
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no
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f85d84c7-bfab-43a6-80be-9a348cad9d88
date added to LUP
2017-10-02 17:28:18
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2017-10-22 05:36:20
@article{f85d84c7-bfab-43a6-80be-9a348cad9d88,
  abstract     = {<p>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.</p>},
  author       = {Lee, Dung Fang and Su, Jie and Ang, Yen Sin and Carvajal-Vergara, Xonia and Mulero-Navarro, Sonia and Pereira, Carlos F. and Gingold, Julian and Wang, Hung Liang and Zhao, Ruiying and Sevilla, Ana and Darr, Henia and Williamson, Andrew J K and Chang, Betty and Niu, Xiaohong and Aguilo, Francesca and Flores, Elsa R. and Sher, Yuh Pyng and Hung, Mien Chie and Whetton, Anthony D. and Gelb, Bruce D. and Moore, Kateri A. and Snoeck, Hans Willem and Ma'Ayan, Avi and Schaniel, Christoph and Lemischka, Ihor R.},
  issn         = {1934-5909},
  language     = {eng},
  month        = {08},
  number       = {2},
  pages        = {179--194},
  publisher    = {Cell Press},
  series       = {Cell Stem Cell},
  title        = {Regulation of embryonic and induced pluripotency by aurora kinase-p53 signaling},
  url          = {http://dx.doi.org/10.1016/j.stem.2012.05.020},
  volume       = {11},
  year         = {2012},
}