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.
authors.affiliation: Department of Developmental and Regenerative Biology and The Black Family Stem Cell Institute, Mount Sinai School of Medicine, New York, NY 10029, USA.
authors.forename: Dung-Fang
authors.initials: DF
authors.lastname: Lee
authors.forename: Jie
authors.initials: J
authors.lastname: Su
authors.forename: Yen-Sin
authors.initials: YS
authors.lastname: Ang
authors.forename: Xonia
authors.initials: X
authors.lastname: Carvajal-Vergara
authors.forename: Sonia
authors.initials: S
authors.lastname: Mulero-Navarro
authors.forename: Carlos F
authors.initials: CF
authors.lastname: Pereira
authors.forename: Julian
authors.initials: J
authors.lastname: Gingold
authors.forename: Hung-Liang
authors.initials: HL
authors.lastname: Wang
authors.forename: Ruiying
authors.initials: R
authors.lastname: Zhao
authors.forename: Ana
authors.initials: A
authors.lastname: Sevilla
authors.forename: Henia
authors.initials: H
authors.lastname: Darr
authors.forename: Andrew J K
authors.initials: AJ
authors.lastname: Williamson
authors.forename: Betty
authors.initials: B
authors.lastname: Chang
authors.forename: Xiaohong
authors.initials: X
authors.lastname: Niu
authors.forename: Francesca
authors.initials: F
authors.lastname: Aguilo
authors.forename: Elsa R
authors.initials: ER
authors.lastname: Flores
authors.forename: Yuh-Pyng
authors.initials: YP
authors.lastname: Sher
authors.forename: Mien-Chie
authors.initials: MC
authors.lastname: Hung
authors.forename: Anthony D
authors.initials: AD
authors.lastname: Whetton
authors.forename: Bruce D
authors.initials: BD
authors.lastname: Gelb
authors.forename: Kateri A
authors.initials: KA
authors.lastname: Moore
authors.forename: Hans-Willem
authors.initials: HW
authors.lastname: Snoeck
authors.forename: Avi
authors.initials: A
authors.lastname: Ma'ayan
authors.forename: Christoph
authors.initials: C
authors.lastname: Schaniel
authors.forename: Ihor R
authors.initials: IR
authors.lastname: Lemischka
mesh_terms: D000818:Animals; D064096:Aurora Kinase A; D064127:Aurora Kinases; D002454:Cell Differentiation; D002460:Cell Line; D049109:Cell Proliferation; D053595:Embryonic Stem Cells / Q000166:cytology / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D010766:Phosphorylation; D039904:Pluripotent Stem Cells / Q000166:cytology / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015398:Signal Transduction; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D014981:Xenopus
chemical_list: D016159:Tumor Suppressor Protein p53; C576917:AURKA protein, human; C576918:Aurka protein, mouse; D064096:Aurora Kinase A; D064127:Aurora Kinases; D017346:Protein Serine-Threonine Kinases