The emerging role of p53 in stem cells

Bonizzi, Giuseppina; Cicalese, Angelo; Insinga, Alessandra; Pelicci, Pier Giuseppe

doi:10.1016/j.molmed.2011.08.002

Cited by 66 publications

(51 citation statements)

References 75 publications

(112 reference statements)

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“…Trp53 À/À mice were originally described as developmentally normal but rapidly succumb to spontaneous cancers (mainly lymphomas and sarcomas) within 6-9 mo after birth (Donehower et al 1992;Jacks et al 1994). p53 has also been implicated in stem cell maintenance and homeostasis (Zheng et al 2008;Cicalese et al 2009;Liu et al 2009;Spike and Wahl 2011;Bonizzi et al 2012). These p53 functions may be of particular relevance to tissues that are known to contain a significant pool of adult stem cells (Uccelli et al 2008;Doulatov et al 2012;).…”

Section: Discussionmentioning

confidence: 99%

The C terminus of p53 regulates gene expression by multiple mechanisms in a target- and tissue-specific manner in vivo

et al. 2013

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The p53 tumor suppressor is a transcription factor that mediates varied cellular responses. The C terminus of p53 is subjected to multiple and diverse post-translational modifications. An attractive hypothesis is that differing sets of combinatorial modifications therein determine distinct cellular outcomes. To address this in vivo, a Trp53ΔCTD/ΔCTD mouse was generated in which the endogenous p53 is targeted and replaced with a truncated mutant lacking the C-terminal 24 amino acids. These Trp53ΔCTD/ΔCTD mice die within 2 wk post-partum with hematopoietic failure and impaired cerebellar development. Intriguingly, the C terminus acts via three distinct mechanisms to control p53-dependent gene expression depending on the tissue. First, in the bone marrow and thymus, the C terminus dampens p53 activity. Increased senescence in the Trp53ΔCTD/ΔCTD bone marrow is accompanied by up-regulation of Cdkn1 (p21). In the thymus, the C-terminal domain negatively regulates p53-dependent gene expression by inhibiting promoter occupancy. Here, the hyperactive p53ΔCTD induces apoptosis via enhanced expression of the proapoptotic Bbc3 (Puma) and Pmaip1 (Noxa). In the liver, a second mechanism prevails, since p53ΔCTD has wild-type DNA binding but impaired gene expression. Thus, the C terminus of p53 is needed in liver cells at a step subsequent to DNA binding. Finally, in the spleen, the C terminus controls p53 protein levels, with the overexpressed p53ΔCTD showing hyperactivity for gene expression. Thus, the C terminus of p53 regulates gene expression via multiple mechanisms depending on the tissue and target, and this leads to specific phenotypic effects in vivo.

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Section: Discussionmentioning

confidence: 99%

The C terminus of p53 regulates gene expression by multiple mechanisms in a target- and tissue-specific manner in vivo

et al. 2013

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“…Till date, few mechanisms of action of lncRNAs in stem cell biology have been investigated. Among them, lncRNA-RoR (Regulator Of Reprogramming or lincRNA-ST8SIA3) is a suppressor of p53 response [46] whereas p53 suppression promotes stem cells expansion by activation of self-renewing divisions, symmetric division, and reprogramming of somatic/progenitor cells in stem cells [47,48]. LncRNA-RoR can also act as an endogenous miR-NA sponge (impairing miR-145 repression) to positively regulate Oct4, Nanog, and Sox2 and promote embryonic stem cell self-renewal [49].…”

Section: S-shipmentioning

confidence: 99%

Enrichment of Human Stem-Like Prostate Cells with s-SHIP Promoter Activity Uncovers a Role in Stemness for the Long Noncoding RNA H19

Roy

Vennin

Brocqueville

et al. 2015

Stem Cells and Development

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Understanding normal and cancer stem cells should provide insights into the origin of prostate cancer and their mechanisms of resistance to current treatment strategies. In this study, we isolated and characterized stem-like cells present in the immortalized human prostate cell line, RWPE-1. We used a reporter system with green fluorescent protein (GFP) driven by the promoter of s-SHIP (for stem-SH2-domain-containing 5¢-inositol phosphatase) whose stem cell-specific expression has been previously shown. We observed that s-SHIP-GFPexpressing RWPE-1 cells showed stem cell characteristics such as increased expression of stem cell surface markers (CD44, CD166, TROP2) and pluripotency transcription factors (Oct4, Sox2), and enhanced sphereforming capacity and resistance to arsenite-induced cell death. Concomitant increased expression of the long noncoding RNA H19 was observed, which prompted us to investigate a putative role in stemness for this oncofetal gene. Targeted suppression of H19 with siRNA decreased Oct4 and Sox2 gene expression and colonyforming potential in RWPE-1 cells. Conversely, overexpression of H19 significantly increased gene expression of these two transcription factors and the sphere-forming capacity of RWPE-1 cells. Analysis of H19 expression in various prostate and mammary human cell lines revealed similarities with Sox2 expression, suggesting that a functional relationship may exist between H19 and Sox2. Collectively, we provide the first evidence that s-SHIP-GFP promoter reporter offers a unique marker for the enrichment of human stem-like cell populations and highlight a role in stemness for the long noncoding RNA H19.

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“…The role of p53 in the regulation of the homeostasis of stem cells has also been recognized. It can restrict the self-renewal of stem cells, inhibit symmetric division and block the reprogramming of somatic/progenitor cells into stem cells (Bonizzi et al, 2012). The loss of p53 will therefore facilitate the development of tumors due to the expansion of stem cells resulting from increased self-renewal and symmetric divisions and the reprogramming of somatic/progenitor cells (Bonizzi et al, 2012).…”

Section: Introductionmentioning

confidence: 99%

Mitophagy Controls the Activities of Tumor Suppressor p53 to Regulate Hepatic Cancer Stem Cells

Li¹,

et al. 2017

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Summary Autophagy is required for benign hepatic tumors to progress into malignant hepatocellular carcinoma. However, the mechanism is unclear. Here we report that mitophagy, the selective removal of mitochondria by autophagy, positively regulates hepatic cancer stem cells (CSCs) by suppressing the tumor suppressor p53. When mitophagy is enhanced, p53 colocalizes with mitochondria and is removed by a mitophagy-dependent manner. However, when mitophagy is inhibited, p53 is phosphorylated at serine-392 by PINK1, a kinase associated with mitophagy, on mitochondria and translocated into the nucleus where it binds to the NANOG promoter to prevent OCT4 and SOX2 transcription factors from activating the expression of NANOG, a transcription factor critical for maintaining the stemness and the self-renewal ability of CSCs, resulting in the reduction of hepatic CSC populations. These results demonstrate that mitophagy controls the activities of p53 to maintain hepatic CSCs and provide an explanation to why autophagy is required to promote hepatocarcinogenesis.

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The emerging role of p53 in stem cells

Cited by 66 publications

References 75 publications

The C terminus of p53 regulates gene expression by multiple mechanisms in a target- and tissue-specific manner in vivo

The C terminus of p53 regulates gene expression by multiple mechanisms in a target- and tissue-specific manner in vivo

Enrichment of Human Stem-Like Prostate Cells with s-SHIP Promoter Activity Uncovers a Role in Stemness for the Long Noncoding RNA H19

Mitophagy Controls the Activities of Tumor Suppressor p53 to Regulate Hepatic Cancer Stem Cells

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