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 Filipe; Gingold, Julian A.; Wang, Hung Liang; Zhao, Ruiying; Sevilla, Ana; Darr, Henia; Williamson, Andrew J.K.; Chang, Betty; Niu, Xiaohong; Aguiló, Francesca; Flores, Elsa R.; Sher, Yuh‐Pyng; Hung, Mien‐Chie; Whetton, Anthony D.; Gelb, Bruce D.; Moore, Kateri; Snoeck, Hans Willem; Ma’ayan, Avi; Schaniel, Christoph; Lemischka, Ihor R.

doi:10.1016/j.stem.2012.05.020

Cited by 132 publications

(153 citation statements)

References 63 publications

(108 reference statements)

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“…Instead, p53 in ESCs has an unorthodox role of inducing differentiation after DNA damage by directly suppressing Nanog, leading to spontaneous differentiation of ESCs into other cell types, which can then undergo efficient p53-dependent cell cycle arrest or apoptosis (40). Mechanisms that control p53 activation to permit rapid ESC cycling without compromising the genomic stability remained unclear until recently when posttranslational mechanisms have been shown to restrict differentiation-inducing p53 activity (55,56). Endogenous ROS, natural byproduct of cellular respiration, is a major source of DNA damage and a substantial factor contributing to genomic instability and accumulation of mutations (57).…”

Section: Resultsmentioning

confidence: 99%

Integrative framework for identification of key cell identity genes uncovers determinants of ES cell identity and homeostasis

Cinghu

Yellaboina

Freudenberg

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Identification of genes associated with specific biological phenotypes is a fundamental step toward understanding the molecular basis underlying development and pathogenesis. Although RNAibased high-throughput screens are routinely used for this task, false discovery and sensitivity remain a challenge. Here we describe a computational framework for systematic integration of published gene expression data to identify genes defining a phenotype of interest. We applied our approach to rank-order all genes based on their likelihood of determining ES cell (ESC) identity. RNAi-mediated loss-of-function experiments on top-ranked genes unearthed many novel determinants of ESC identity, thus validating the derived gene ranks to serve as a rich and valuable resource for those working to uncover novel ESC regulators. Underscoring the value of our gene ranks, functional studies of our top-hit Nucleolin (Ncl), abundant in stem and cancer cells, revealed Ncl's essential role in the maintenance of ESC homeostasis by shielding against differentiation-inducing redox imbalance-induced oxidative stress. Notably, we report a conceptually novel mechanism involving a Nucleolin-dependent Nanog-p53 bistable switch regulating the homeostatic balance between self-renewal and differentiation in ESCs. Our findings connect the dots on a previously unknown regulatory circuitry involving genes associated with traits in both ESCs and cancer and might have profound implications for understanding cell fate decisions in cancer stem cells. The proposed computational framework, by helping to prioritize and preselect candidate genes for tests using complex and expensive genetic screens, provides a powerful yet inexpensive means for identification of key cell identity genes.C ell identity is governed by a set of key regulators, which maintain the gene expression program characteristic of that cell state while restricting the induction of alternate programs that could lead to a new cell state. Identification of cell identity genes is a fundamental step toward understanding the mechanisms that underlie cellular homeostasis, differentiation, development, and pathogenesis. RNAi-based high-throughput screening has become a widely used method for identification of new components of diverse biological processes, including signal transduction, cancer, and host cell responses to infection (1, 2). Genome-scale RNAi screens have led to identification of tumor suppressors (3), oncogenes (4), therapeutic targets (5), and regulators of ES cell (ESC) maintenance (6-10), tissue regeneration (11), viral infection (12), and antiviral response (13).Despite the success of RNAi screens, false discovery and sensitivity remain a significant and difficult problem to address, with surprisingly small overlap among screen hits from independent but related screens (1). For example, multiple genomescale RNAi screens for host proteins required for HIV infection/ replication resulted in a limited overlap among screen hits at the gene level (1). Similarly, screens performed in mous...

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Section: Resultsmentioning

confidence: 99%

Integrative framework for identification of key cell identity genes uncovers determinants of ES cell identity and homeostasis

Cinghu

Yellaboina

Freudenberg

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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“…Aurora-A also has an essential role in the regulation of self-renewal of embryonic stem cells and in the development of induced pluripotent stem cells (11). These findings suggest that Aurora-A is critical in driving and/or maintenance of stem cell-like phenotype in pluripotent stem cells and CSCs.…”

Section: Blg-aurora-a Transgene-induced Emt In Mouse Mammary Tumor Cementioning

confidence: 87%

“…Aurora-A functional studies have demonstrated that Aurora-A phosphorylation of tumor-suppressor proteins p53 and p73 result in their loss of functions in high Aurora-A-expressing cells acquiring resistance to DNA-and spindle-damaging agents due to override of the respective checkpoint response pathways (8)(9)(10). Furthermore, Aurora-A phosphorylation of p53 was shown to be critical in the maintenance of self-renewal and pluripotency of embryonic stem cells as well as in the reprogramming of induced pluripotent stem cells (11). It has been proposed that cancer stem cells (CSCs) may be derived either from somatic stem cells or from differentiated cells through an epithelial-to-mesenchymal transition (EMT) reprogramming process (12,13), which may involve Aurora-A-p53 signaling axis because Aurora-A overexpression was correlated with resistance to anticancer drugs in tumors, a hallmark of CSCs (14).…”

Section: Introductionmentioning

confidence: 99%

Aurora kinase-A overexpression in mouse mammary epithelium induces mammary adenocarcinomas harboring genetic alterations shared with human breast cancer

Treekitkarnmongkol

Katayama

Kai

et al. 2016

CARCIN

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Recent data from The Cancer Genome Atlas analysis have revealed that Aurora kinase A (AURKA) amplification and overexpression characterize a distinct subset of human tumors across multiple cancer types. Although elevated expression of AURKA has been shown to induce oncogenic phenotypes in cells in vitro, findings from transgenic mouse models of Aurora-A overexpression in mammary glands have been distinct depending on the models generated. In the present study, we report that prolonged overexpression of AURKA transgene in mammary epithelium driven by ovine β-lactoglobulin promoter, activated through multiple pregnancy and lactation cycles, results in the development of mammary adenocarcinomas with alterations in cancer-relevant genes and epithelial-to-mesenchymal transition. The tumor incidence was 38.9% (7/18) in Aurora-A transgenic mice at 16 months of age following 4-5 pregnancy cycles. Aurora-A overexpression in the tumor tissues accompanied activation of Akt, elevation of Cyclin D1, Tpx2 and Plk1 along with downregulation of ERα and p53 proteins, albeit at varying levels. Microarray comparative genomic hybridization (CGH) analyses of transgenic mouse mammary adenocarcinomas revealed copy gain of Glp1r and losses of Ercc5, Pten and Tcf7l2 loci. Review of human breast tumor transcriptomic data sets showed association of these genes at varying levels with Aurora-A gain of function alterations. Whole exome sequencing of the mouse tumors also identified gene mutations detected in Aurora-A overexpressing human breast cancers. Our findings demonstrate that prolonged overexpression of Aurora-A can be a driver somatic genetic event in mammary adenocarcinomas associated with deregulated tumor-relevant pathways in the Aurora-A subset of human breast cancer.

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“…Physiological down-regulation of p53 has been previously reported in human embryonic stem cells exposed to hypoxia, where it leads to a state of "enhanced stemness" (32), and during development in Xenopus, where it is required for maintaining ectodermal cells in a pluripotent state (33). Furthermore, inhibition of p53 activity by AurK is crucial for the maintenance of both embryonic and induced pluripotency (34), and during induced pluripotent stem cell induction the reprogramming process itself leads to p53 down-regulation (15). These studies indicate a connection between p53 down-regulation and the reversal of the differentiated state.…”

Section: Salamander δNp73 Acts As a P53 Dominant-negative And Its Modmentioning

confidence: 91%

Regulation of p53 is critical for vertebrate limb regeneration

Yun

Gates

Brockes

2013

Proc. Natl. Acad. Sci. U.S.A.

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Extensive regeneration of the vertebrate body plan is found in salamander and fish species. In these organisms, regeneration takes place through reprogramming of differentiated cells, proliferation, and subsequent redifferentiation of adult tissues. Such plasticity is rarely found in adult mammalian tissues, and this has been proposed as the basis of their inability to regenerate complex structures. Despite their importance, the mechanisms underlying the regulation of the differentiated state during regeneration remain unclear. Here, we analyzed the role of the tumor-suppressor p53 during salamander limb regeneration. The activity of p53 initially decreases and then returns to baseline. Its down-regulation is required for formation of the blastema, and its upregulation is necessary for the redifferentiation phase. Importantly, we show that a decrease in the level of p53 activity is critical for cell cycle reentry of postmitotic, differentiated cells, whereas an increase is required for muscle differentiation. In addition, we have uncovered a potential mechanism for the regulation of p53 during limb regeneration, based on its competitive inhibition by ΔNp73. Our results suggest that the regulation of p53 activity is a pivotal mechanism that controls the plasticity of the differentiated state during regeneration. myogenesis | chondrogenesis | p73 | carcinogenesis U nlike mammals, which exhibit limited regenerative abilities, the urodele amphibians-or salamanders-are capable of regenerating an extraordinary range of body structures, including ocular tissues, tail, sections of the heart, parts of the nervous system, and entire limbs (1). In salamanders, such as the newt and axolotl, limb regeneration depends on the formation of a blastema, a mound of progenitor cells of restricted potential that arises after amputation (2-4). Following a period of proliferation, blastema cells redifferentiate and restore the structures of the limb.Extensive evidence indicates that limb regeneration depends on reprogramming of cells in mature limb tissues. Upon amputation, muscle, cartilage, and connective tissue cells underneath the injury site lose their differentiated characteristics and reenter the cell cycle to give rise to the blastema (5-8). This mechanism has also been observed during zebrafish heart and fin regeneration (9, 10). In contrast, reversals of the differentiated state are rarely observed in mammalian tissues, which led to the suggestion that inability to undergo dedifferentiation could contribute to the failure of regeneration in mammals (11). Despite their significance, the mechanisms underlying regulation of the differentiated state during vertebrate regeneration remain poorly understood.Recently, the tumor suppressor p53, whose best-characterized functions are in the maintenance of genome stability (12), has been implicated in the suppression of artificial cell reprogramming to pluripotency (13-17) and the promotion of differentiation pathways in mammals (18). In addition, it has been observed that inhibiting p...

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Regulation of Embryonic and Induced Pluripotency by Aurora Kinase-p53 Signaling

Cited by 132 publications

References 63 publications

Integrative framework for identification of key cell identity genes uncovers determinants of ES cell identity and homeostasis

Integrative framework for identification of key cell identity genes uncovers determinants of ES cell identity and homeostasis

Aurora kinase-A overexpression in mouse mammary epithelium induces mammary adenocarcinomas harboring genetic alterations shared with human breast cancer

Regulation of p53 is critical for vertebrate limb regeneration

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