p53 regulates the mevalonate pathway in human glioblastoma multiforme

Laezza, Chiara; Am, D'Alessandro; Croce, Luciano Di; Picardi, Paola; Ciaglia, Elena; Pisanti, Simona; Malfitano, Anna Maria; Comegna, Marika; Faraonio, Raffaella; Gazzerro, Patrizia; Bifulco, Maurizio

doi:10.1038/cddis.2015.279

Cited by 42 publications

(43 citation statements)

References 40 publications

(40 reference statements)

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“…Similar to PLA2R1 inactivation, p53DN also reduced the frequency of misshapen nuclei and FDPS expression in progerin‐expressing cells (Figure 6b–e). Furthermore, p53 activation by nutlin‐3, a known activator of p53 (Vassilev et al, 2004), led to increased FDPS mRNA similar to the observed p21 increase and led to binding of p53 on the p53 binding site previously described on FDPS promoter in cancer cells (Laezza et al, 2015; Figure 6f–g). The results suggest that p53 contributes to progerin/PLA2R1‐induced misshapen nuclei and cellular senescence by upregulating FDPS expression.…”

Section: Resultssupporting

confidence: 79%

“…p53 also contributes to progerin‐induced senescence, and it may regulate FDPS expression in cancer cells (Kudlow, Stanfel, Burtner, Johnston, & Kennedy, 2008; Laezza et al., 2015). However, whether p53 affects nuclear shape and whether it regulates FDPS expression in noncancer cells is not clear.…”

Section: Resultsmentioning

confidence: 99%

“…DNA damage signaling leads to phosphorylation and activation of p53 transcriptional activity, both being observed in progerin‐expressing cells and reversed in PLA2R1 knockdown cells. p53 has been reported to impact progerin‐induced senescence (Kudlow et al, 2008) and once to bind to the FDPS promoter and to regulate FDPS expression in cancer cells (Laezza et al, 2015). Thus, it is conceivable that p53 downstream of progerin and PLA2R1 could mediate the increased FDPS expression.…”

Section: Discussionmentioning

confidence: 99%

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Targeting the phospholipase A2 receptor ameliorates premature aging phenotypes

et al. 2018

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Hutchinson–Gilford progeria syndrome (HGPS) is a lethal premature aging that recapitulates many normal aging characteristics. This disorder is caused by mutation in the LMNA gene leading to the production of progerin which induces misshapen nuclei, cellular senescence, and aging. We previously showed that the phospholipase A2 receptor (PLA2R1) promotes senescence induced by replicative, oxidative, and oncogenic stress but its role during progerin‐induced senescence and in progeria is currently unknown. Here, we show that knockdown of PLA2R1 prevented senescence induced by progerin expression in human fibroblasts and markedly delayed senescence of HGPS patient‐derived fibroblasts. Whole‐body knockout of Pla2r1 in a mouse model of progeria decreased some premature aging phenotypes, such as rib fracture and decreased bone content, together with decreased senescence marker. Progerin‐expressing human fibroblasts exhibited a high frequency of misshapen nuclei and increased farnesyl diphosphate synthase (FDPS) expression compared to controls; knockdown of PLA2R1 reduced the frequency of misshapen nuclei and normalized FDPS expression. Pamidronate, a FDPS inhibitor, also reduced senescence and misshapen nuclei. Downstream of PLA2R1, we found that p53 mediated the progerin‐induced increase in FDPS expression and in misshapen nuclei. These results suggest that PLA2R1 mediates key premature aging phenotypes through a p53/FDPS pathway and might be a new therapeutic target.

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Section: Resultssupporting

confidence: 79%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Targeting the phospholipase A2 receptor ameliorates premature aging phenotypes

et al. 2018

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“…p53 induces the expression of several proteins involved in melavonate production such as HMGCR and LDLR (low-density lipoprotein receptor), which are upregulated at basal levels in GBM cells compared to normal astrocytes (Laezza et al, 2015). This may represent another pathway by which functional p53 may be able to overcome proliferative defects, as cholesterol is required for DNA synthesis and proliferation.…”

Section: P53 Mutations Affect Not Only Cell Cycle Checkpoints But Alsmentioning

confidence: 99%

Metabolic Reprogramming in Glioma

Strickland

Stoll

2017

Front. Cell Dev. Biol.

266

269

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Many cancers have long been thought to primarily metabolize glucose for energy production—a phenomenon known as the Warburg Effect, after the classic studies of Otto Warburg in the early twentieth century. Yet cancer cells also utilize other substrates, such as amino acids and fatty acids, to produce raw materials for cellular maintenance and energetic currency to accomplish cellular tasks. The contribution of these substrates is increasingly appreciated in the context of glioma, the most common form of malignant brain tumor. Multiple catabolic pathways are used for energy production within glioma cells, and are linked in many ways to anabolic pathways supporting cellular function. For example: glycolysis both supports energy production and provides carbon skeletons for the synthesis of nucleic acids; meanwhile fatty acids are used both as energetic substrates and as raw materials for lipid membranes. Furthermore, bio-energetic pathways are connected to pro-oncogenic signaling within glioma cells. For example: AMPK signaling links catabolism with cell cycle progression; mTOR signaling contributes to metabolic flexibility and cancer cell survival; the electron transport chain produces ATP and reactive oxygen species (ROS) which act as signaling molecules; Hypoxia Inducible Factors (HIFs) mediate interactions with cells and vasculature within the tumor environment. Mutations in the tumor suppressor p53, and the tricarboxylic acid cycle enzymes Isocitrate Dehydrogenase 1 and 2 have been implicated in oncogenic signaling as well as establishing metabolic phenotypes in genetically-defined subsets of malignant glioma. These pathways critically contribute to tumor biology. The aim of this review is two-fold. Firstly, we present the current state of knowledge regarding the metabolic strategies employed by malignant glioma cells, including aerobic glycolysis; the pentose phosphate pathway; one-carbon metabolism; the tricarboxylic acid cycle, which is central to amino acid metabolism; oxidative phosphorylation; and fatty acid metabolism, which significantly contributes to energy production in glioma cells. Secondly, we highlight processes (including the Randle Effect, AMPK signaling, mTOR activation, etc.) which are understood to link bio-energetic pathways with oncogenic signals, thereby allowing the glioma cell to achieve a pro-malignant state.

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“…1, 2, 3, 4, 5, 6, 7 Often referred to as the guardian of the genome, its role in protecting the cell from accumulation of DNA damage by inducing DNA repair or cell death is well-studied. 8, 9, 10, 11, 12 However, p53 has also been implicated in a vast variety of other cell pathways, including metabolism, 13 autophagy, 14, 15 mitochondrial function 16, 17, 18 and also cell differentiation and pluripotency.…”

mentioning

confidence: 99%

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

et al. 2016

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The tumour suppressor p53 plays an important role in somatic cell reprogramming. While wild-type p53 reduces reprogramming efficiency, mutant p53 exerts a gain of function activity that leads to increased reprogramming efficiency. Furthermore, induced pluripotent stem cells expressing mutant p53 lose their pluripotency in vivo and form malignant tumours when injected in mice. It is therefore of great interest to identify targets of p53 (wild type and mutant) that are responsible for this phenotype during reprogramming, as these could be exploited for therapeutic use, that is, formation of induced pluripotent stem cells with high reprogramming efficiency, but no oncogenic potential. Here we studied the transcriptional changes of microRNA in a series of mouse embryonic fibroblasts that have undergone transition to induced pluripotent stem cells with wild type, knock out or mutant p53 status in order to identify microRNAs whose expression during reprogramming is dependent on p53. We identified a number of microRNAs, with known functions in differentiation and carcinogenesis, the expression of which was dependent on the p53 status of the cells. Furthermore, we detected several uncharacterised microRNAs that were regulated differentially in the different p53 backgrounds, suggesting a novel role of these microRNAs in reprogramming and pluripotency.

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p53 regulates the mevalonate pathway in human glioblastoma multiforme

Cited by 42 publications

References 40 publications

Targeting the phospholipase A2 receptor ameliorates premature aging phenotypes

Targeting the phospholipase A2 receptor ameliorates premature aging phenotypes

Metabolic Reprogramming in Glioma

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

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