Differential regulated microRNA by wild type and mutant p53 in induced pluripotent stem cells

Grespi, Francesca; Landré, Vivien; Molchadsky, Alina; Daniele, Nicola Di; Marsella, Lt; Melino, Gerry; Rotter, Varda

doi:10.1038/cddis.2016.419

Cited by 17 publications

(14 citation statements)

References 89 publications

(103 reference statements)

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“…Furthermore, while reprogrammed cells with p53 deficiency formed differentiated teratomas in vivo , those with GOF mutant p53 formed undifferentiated malignant tumors, implying that it confers oncogenic properties to the reprogrammed cells ( 186 ). A few years later, Grespi et al identified a set of miRNAs whose expression altered in a p53-dependent manner during transition of mouse embryonic fibroblasts to induced pluripotent stem cells ( 187 ). The role of these miRNAs can further be investigated to determine their role in regulation of mutant p53 driven stemness.…”

Section: P53 Mutation Imparts Stem-like Properties To Cancer Cellsmentioning

confidence: 99%

Cancer Stemness: p53 at the Wheel

2021

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The tumor suppressor p53 maintains an equilibrium between self-renewal and differentiation to sustain a limited repertoire of stem cells for proper development and maintenance of tissue homeostasis. Inactivation of p53 disrupts this balance and promotes pluripotency and somatic cell reprogramming. A few reports in recent years have indicated that prevalent TP53 oncogenic gain-of-function (GOF) mutations further boosts the stemness properties of cancer cells. In this review, we discuss the role of wild type p53 in regulating pluripotency of normal stem cells and various mechanisms that control the balance between self-renewal and differentiation in embryonic and adult stem cells. We also highlight how inactivating and GOF mutations in p53 stimulate stemness in cancer cells. Further, we have explored the various mechanisms of mutant p53-driven cancer stemness, particularly emphasizing on the non-coding RNA mediated epigenetic regulation. We have also analyzed the association of cancer stemness with other crucial gain-of-function properties of mutant p53 such as epithelial to mesenchymal transition phenotypes and chemoresistance to understand how activation of one affects the other. Given the critical role of cancer stem-like cells in tumor maintenance, cancer progression, and therapy resistance of mutant p53 tumors, targeting them might improve therapeutic efficacy in human cancers with TP53 mutations.

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Section: P53 Mutation Imparts Stem-like Properties To Cancer Cellsmentioning

confidence: 99%

Cancer Stemness: p53 at the Wheel

2021

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“…The result was that mutant p53 RNA expression signature was involved in the prognostic predictions in 11 different cancers [11]. Therefore, miRNAs participate in the suppression or induction of tumor development depending on the wt-or mut-p53 cell context [11,46].…”

Section: Mutant P53 and Mirnasmentioning

confidence: 99%

“…mut-p53 affects miRNA expression by inhibiting those which play a tumor-suppressing role and inducing those which have oncogenic potential [46].…”

Section: Mirnas Induced By Mutant P53mentioning

confidence: 99%

The Impact of Mutant p53 in the Non-Coding RNA World

Agostino

2020

Biomolecules

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Long non-coding RNAs (lncRNAs), circular RNAs (circRNAs), micro RNAs (miRNAs), and extracellular RNAs (exRNAs) are new groups of RNAs with regulation activities that have low or no protein-coding ability. Emerging evidence suggests that deregulated expression of these non-coding RNAs is associated with the induction and progression of diverse tumors throughout epigenetic, transcriptional, and post-transcriptional modifications. A consistent number of non-coding RNAs (ncRNAs) has been shown to be regulated by p53, the most important tumor suppressor of the cells frequently mutated in human cancer. It has been shown that some mutant p53 proteins are associated with the loss of tumor suppressor activity and the acquisition of new oncogenic functions named gain-of-function activities. In this review, we highlight recent lines of evidence suggesting that mutant p53 is involved in the expression of specific ncRNAs to gain oncogenic functions through the creation of a complex network of pathways that influence each other.Biomolecules 2020, 10, 472 2 of 15 heterotetrameric mut-p53/wt-p53 complex can inhibit the function of the remaining wt-p53 in tumor suppression [8,9]. Most of the missense mutations occur in the p53 DNA-binding region and can be classified as either contact mutations (as p53R248 and p53R273 interfere directly with DNA binding) or conformational mutations (as p53R175 induces local or global conformational distortions) [5,9].Six hotspot mutations are the most represented in the cancers. These include R175, G245, R248, R249, R273, and R282, which make up about 30% of all mutations in TP53 covering all human cancer types [8][9][10]. However, due to cancer genome sequencing tools, many other different TP53 mutations have been discovered. mut-p53 GOF has been demonstrated by numerous cell-based experiments such as by ectopic expression of mut-p53 proteins in p53-null human tumor cells or knockdown of endogenous mut-p53 in cells containing only one allele of mutant p53, as well as in mutant p53 knock-in mouse models [5,[8][9][10]. Genome sequencencing has highlighted that more than 91% of TP53-mutant cancers exhibit loss of the second allele (LOH) by mutation or DNA deletion [11].Many mut-p53 GOF activities have been identified as tumor cell proliferation, survival, migration and invasion, enhancing chemoresistance, disrupting proper tissue architecture, inducing cancer metabolism (Warburg effect and lipid metabolism), and increasing genomic instability and mitochondrial dysfunction [5,[10][11][12][13][14][15] (Figure 1).

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“…One of the principal negative regulators of pluripotency is the tumor suppressor protein, TP53 (Kim et al, 2011;Spike and Wahl, 2011). TP53 exerts its anti-proliferative functions mostly as a transcription factor by controlling both the expression of coding and non-coding RNAs (Lezina et al, 2013;Marouco et al, 2013;Grespi et al, 2016). p53 was shown to repress transcription of the master regulators of pluripotency, Nanog and Oct4 (Lin et al, 2005;Qin et al, 2007) (Figure 1).…”

Section: Ca 2þ Regulation Of Tp53 and Pluripotency Of Escsmentioning

confidence: 99%

Ca²⁺‐depended signaling pathways regulate self‐renewal and pluripotency of stem cells

Ермаков

Daks

Fedorova

et al. 2018

Cell Biology International

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Ca -mediated signaling is widely spread in nature and plays critical role in the individual development of various organisms ranging from microorganisms to mammals. In vertebrates, Ca is involved in important developmental events: fertilization, body plan establishment, and organogenesis. The two later events are defined by embryonic stem cells (ESCs). ESCs are capable of self-renewal and are pluripotent by nature, that is, can give rise to all types of cells that make up the body. Given the paramount importance of Ca signalization in the development, it is therefore not surprising this process also plays role in the biology of stem cells. In this review, we scrutinize the published experimental data on the role of Ca ions in embryonic stem cells self-renewal and pluripotency. In line with this, we also discuss possible mechanisms of p53 inhibition as a major hindrance to self-renewal of ESCs. Finally, we argue about the role of G-protein-coupled receptors (GPCRs), the largest family of heteromeric transmembrane receptors, and GPCR-mediated signalization in stem cells, and propose the role for the GPCR-G-protein-PLC-Ca -downstream signaling pathway in the regulation of pluripotency of both mouse and human ESCs.

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Differential regulated microRNA by wild type and mutant p53 in induced pluripotent stem cells

Cited by 17 publications

References 89 publications

Cancer Stemness: p53 at the Wheel

Cancer Stemness: p53 at the Wheel

The Impact of Mutant p53 in the Non-Coding RNA World

Ca²⁺‐depended signaling pathways regulate self‐renewal and pluripotency of stem cells

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Differential regulated microRNA by wild type and mutant p53 in induced pluripotent stem cells

Cited by 17 publications

References 89 publications

Cancer Stemness: p53 at the Wheel

Cancer Stemness: p53 at the Wheel

The Impact of Mutant p53 in the Non-Coding RNA World

Ca2+‐depended signaling pathways regulate self‐renewal and pluripotency of stem cells

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Ca²⁺‐depended signaling pathways regulate self‐renewal and pluripotency of stem cells