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

Dung Fang Lee; Jie Su; Yen Sin Ang; Xonia Carvajal-Vergara; Sonia Mulero-Navarro; Carlos F. Pereira; 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

doi:10.1016/j.stem.2012.05.020

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

Dung Fang Lee, Jie Su, Yen Sin Ang, Xonia Carvajal-Vergara, Sonia Mulero-Navarro, Carlos F. Pereira, 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. GelbKateri A. Moore, Hans Willem Snoeck, Avi Ma'Ayan, Christoph Schaniel, Ihor R. Lemischka

Research output: Contribution to journal › Article › peer-review

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. © 2012 Elsevier Inc.

Original language	English
Pages (from-to)	179-194
Number of pages	15
Journal	Cell Stem Cell
Volume	11
Issue number	2
DOIs	https://doi.org/10.1016/j.stem.2012.05.020
Publication status	Published - 3 Aug 2012

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10.1016/j.stem.2012.05.020

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Lee, D. F., Su, J., Ang, Y. S., Carvajal-Vergara, X., Mulero-Navarro, S., Pereira, C. F., Gingold, J., Wang, H. L., Zhao, R., Sevilla, A., Darr, H., Williamson, A. J. K., Chang, B., Niu, X., Aguilo, F., Flores, E. R., Sher, Y. P., Hung, M. C., Whetton, A. D., ... Lemischka, I. R. (2012). Regulation of embryonic and induced pluripotency by aurora kinase-p53 signaling. Cell Stem Cell, 11(2), 179-194. https://doi.org/10.1016/j.stem.2012.05.020

@article{455f2153608947159a9d3001e4445bb8,

title = "Regulation of embryonic and induced pluripotency by aurora kinase-p53 signaling",

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. {\textcopyright} 2012 Elsevier Inc.",

author = "Lee, {Dung Fang} and Jie Su and Ang, {Yen Sin} and Xonia Carvajal-Vergara and Sonia Mulero-Navarro and Pereira, {Carlos F.} and Julian Gingold and Wang, {Hung Liang} and Ruiying Zhao and Ana Sevilla and Henia Darr and Williamson, {Andrew J K} and Betty Chang and Xiaohong Niu and Francesca Aguilo 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 Avi Ma'Ayan and Christoph Schaniel and Lemischka, {Ihor R.}",

note = "5R01GM078465, NIGMS NIH HHS, United StatesP50 GM071558, NIGMS NIH HHS, United StatesR01 GM078465, NIGMS NIH HHS, United StatesR01 GM098316, NIGMS NIH HHS, United States",

year = "2012",

month = aug,

day = "3",

doi = "10.1016/j.stem.2012.05.020",

language = "English",

volume = "11",

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journal = "Cell Stem Cell",

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Lee, DF, Su, J, Ang, YS, Carvajal-Vergara, X, Mulero-Navarro, S, Pereira, CF, Gingold, J, Wang, HL, Zhao, R, Sevilla, A, Darr, H, Williamson, AJK, Chang, B, Niu, X, Aguilo, F, Flores, ER, Sher, YP, Hung, MC, Whetton, AD, Gelb, BD, Moore, KA, Snoeck, HW, Ma'Ayan, A, Schaniel, C & Lemischka, IR 2012, 'Regulation of embryonic and induced pluripotency by aurora kinase-p53 signaling', Cell Stem Cell, vol. 11, no. 2, pp. 179-194. https://doi.org/10.1016/j.stem.2012.05.020

TY - JOUR

T1 - Regulation of embryonic and induced pluripotency by aurora kinase-p53 signaling

AU - Lee, Dung Fang

AU - Su, Jie

AU - Ang, Yen Sin

AU - Carvajal-Vergara, Xonia

AU - Mulero-Navarro, Sonia

AU - Pereira, Carlos F.

AU - Gingold, Julian

AU - Wang, Hung Liang

AU - Zhao, Ruiying

AU - Sevilla, Ana

AU - Darr, Henia

AU - Williamson, Andrew J K

AU - Chang, Betty

AU - Niu, Xiaohong

AU - Aguilo, Francesca

AU - Flores, Elsa R.

AU - Sher, Yuh Pyng

AU - Hung, Mien Chie

AU - Whetton, Anthony D.

AU - Gelb, Bruce D.

AU - Moore, Kateri A.

AU - Snoeck, Hans Willem

AU - Ma'Ayan, Avi

AU - Schaniel, Christoph

AU - Lemischka, Ihor R.

N1 - 5R01GM078465, NIGMS NIH HHS, United StatesP50 GM071558, NIGMS NIH HHS, United StatesR01 GM078465, NIGMS NIH HHS, United StatesR01 GM098316, NIGMS NIH HHS, United States

PY - 2012/8/3

Y1 - 2012/8/3

N2 - 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. © 2012 Elsevier Inc.

AB - 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. © 2012 Elsevier Inc.

U2 - 10.1016/j.stem.2012.05.020

DO - 10.1016/j.stem.2012.05.020

M3 - Article

C2 - 22862944

SN - 1934-5909

VL - 11

SP - 179

EP - 194

JO - Cell Stem Cell

JF - Cell Stem Cell

IS - 2

ER -

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

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