The p53 Family Coordinates Wnt and Nodal Inputs in Mesendodermal Differentiation of Embryonic Stem Cells

Wang, Qiong; Zou, Yilong; Nowotschin, Sonja; Kim, Sang Yong; Li, Qing V.; Soh, Chew-Li; Su, Jie; Zhang, Chao; Shu, Weiqun; Xi, Qiaoran; Huangfu, Danwei; Hadjantonakis, Anna-Katerina; Massagué, Joan

doi:10.1016/j.stem.2016.10.002

Cited by 140 publications

(169 citation statements)

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“…In addition to the well-known proapoptotic effect of robust p53 activation, p53 has also been shown to be a transcription factor involved in many biological processes (13)(14)(15) , including osteogenic differentiation (2). In this study, we firstly examined the p53 expression and activation in pAVICs after warfarin treatment, we found that warfarin treatment slightly increased the mRNA and protein levels of p53 ( Fig.…”

Section: Low-level Increase Of P53 Promotes Warfarininduced Pavic Calmentioning

confidence: 89%

Low-level overexpression of p53 promotes warfarin-induced calcification of porcine aortic valve interstitial cells by activating Slug gene transcription

Gao¹,

Ji²,

Lü³

et al. 2018

Journal of Biological Chemistry

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The most frequently used oral anti-coagulant warfarin has been implicated in inducing calcification of aortic valve interstitial cells (AVICs), while the mechanism is not fully understood. The low-level activation of p53 is found to be involved in osteogenic transdifferentiation and calcification of AVICs. Whether p53 participating in warfarin-induced AVIC calcification remains unknown. In this study, we investigated the role of low-level p53 overexpression in warfarin-induced porcine AVIC (pAVIC) calcification.Immunostaining, quantitative PCR and western blotting revealed that p53 was expressed in human and pAVICs and that p53 expression was slightly increased in calcific human aortic valves compared with non-calcific valves. TUNEL staining indicated that apoptosis slightly increased in calcific aortic valves than in non-calcific valves. Warfarin treatment led to lowlevel increase of p53 mRNA and protein both in pAVICs and mouse aortic valves. Low-level overexpression of p53 in pAVICs via an adenovirus vector did not affect pAVIC apoptosis, but promoted warfarin-induced calcium deposition and expression of osteogenic markers. shRNAmediated p53 knockdown attenuated the pAVIC calcium deposition and osteogenic marker expression. Moreover, ChIP and luciferase assays showed that p53 was recruited to the slug promoter and activated slug expression in calcific pAVICs. Of note, overexpression of Slug increased osteogenic marker Runx2 expression, but not pAVIC calcium deposition, and Slug knockdown attenuated pAVIC calcification and p53-mediated pAVIC calcium deposition and expression of osteogenic markers. In conclusion, we found that p53 plays an important role in warfarin induced pAVIC calcification and increased slug transcription by p53 is required for p53-mediated pAVIC calcification.The tumor suppressor p53 plays important roles in cell cycle regulation, apoptosis, and DNA p53 and aortic valve interstitial cell calcification 2 damage (1), as well as in osteoblastic differentiation and bone development. Deletion of the p53 inhibitor MDM2 in osteoblast lineage cells leads to increased p53 production and suppression of bone organogenesis and homeostasis, whereas deletion of p53 accelerates osteoblast cell differentiation and bone formation (2,3). In addition, using p53 knockout mice with chronic kidney disease, Li, KL, et al. showed that p53 negatively regulates osteogenic differentiation of vascular smooth muscle cells and aortic calcification suggesting the p53 is involved in pathological tissue calcification (4).The vitamin K antagonist, warfarin, is the most frequently used oral anti-coagulant to treat thromboprophylaxis in the presence of atrial fibrillation or a mechanical prosthetic heart valve. Recently, human and animal studies have implicated warfarin use with vascular and valvular calcification. Long-term warfarin treatment impairs vitamin K-dependent modification of many proteins, including matrix gla protein (MGP), inhibits the bone morphogenetic protein 2 (BMP2) and bone morphogenetic protein...

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Section: Low-level Increase Of P53 Promotes Warfarininduced Pavic Calmentioning

confidence: 89%

Low-level overexpression of p53 promotes warfarin-induced calcification of porcine aortic valve interstitial cells by activating Slug gene transcription

Gao¹,

Ji²,

Lü³

et al. 2018

Journal of Biological Chemistry

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“…For example, CRISPR‐Cas9 was used to delete or inhibit a specific messenger RNA modification N6‐methyl‐adenosine to study the mammalian developmental, disease‐related mechanism in both human and mouse embryonic stem cells . Another study used CRISPR‐Cas9 to knock out three proteins ( p53 , p63 and p73 ) in the tumour suppressor family to study the involvement of these proteins in mouse development …”

Section: Mechanisms Of Gene Editingmentioning

confidence: 99%

“…7 Another study used CRISPR-Cas9 to knock out three proteins (p53, p63 and p73) in the tumour suppressor family to study the involvement of these proteins in mouse development. 31 In contrast to the NHEJ pathway, HDR can precisely repair the DSB by inserting a donor DNA sequence inbetween the DSB, where flanking homology regions are present in both sequences. 18,21,22,32 Since wide adoption, the field has made significant strides in improving the specificity by increasing the HDR:NHEJ ratio.…”

Section: Mechanisms Of Gene Editingmentioning

confidence: 99%

Gene editing of stem cells for kidney disease modelling and therapeutic intervention

2018

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Recent developments in targeted gene editing have paved the way for the wide adoption of clustered regularly interspaced short palindromic repeats (CRISPR)-associated protein-9 nucleases (Cas9) as an RNA-guided molecular tool to modify the genome of eukaryotic cells of animals. Theoretically, the translation of CRISPR-Cas9 can be applied to the treatment of inherited or acquired kidney disease, kidney transplantation and genetic corrections of somatic cells from kidneys with inherited mutations, such as polycystic kidney disease. Human pluripotent stem cells have been used to generate an unlimited source of kidney progenitor cells or, when spontaneously differentiated into three-dimensional kidney organoids, to model kidney organogenesis or the pathogenesis of disease. Gene editing now allows for the tagging and selection of specific kidney cell types or disease-specific gene knock in/out, which enables more precise understanding of kidney organogenesis and genetic diseases. This review discusses the mechanisms of action, in addition to the advantages and disadvantages, of the three major gene editing technologies, namely, CRISPR-Cas9, zinc finger nucleases and transcription activator-like effector nucleases. The implications of using gene editing to better understand kidney disease is reviewed in detail. In addition, the ethical issues of gene editing, which could be easily neglected in the modern, fast-paced research environment, are highlighted.

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“…In the January issue of Cell Stem Cell, Wang et al unequivocally demonstrated that p53 family proteins function as key regulators for the onset of ESC differentiation towards mesendodermal cells (4). Involvement of p53 in early embryogenesis has been previously suggested from analyses of Xenopus embryos in which depletion of p53 renders the embryos refractory to gastrulation (5).…”

mentioning

confidence: 98%

Discovery of a new role for the p53 family in the onset of mesendodermal differentiation of embryonic stem cells

Okuda

Uranishi

Suzuki

2017

Stem Cell Investig.

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The p53 Family Coordinates Wnt and Nodal Inputs in Mesendodermal Differentiation of Embryonic Stem Cells

Cited by 140 publications

References 71 publications

Low-level overexpression of p53 promotes warfarin-induced calcification of porcine aortic valve interstitial cells by activating Slug gene transcription

Low-level overexpression of p53 promotes warfarin-induced calcification of porcine aortic valve interstitial cells by activating Slug gene transcription

Gene editing of stem cells for kidney disease modelling and therapeutic intervention

Discovery of a new role for the p53 family in the onset of mesendodermal differentiation of embryonic stem cells

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