The p53 Family: A Role in Lipid and Iron Metabolism

Laubach, Kyra; Zhang, Jin; Chen, Xinbin

doi:10.3389/fcell.2021.715974

Cited by 20 publications

(12 citation statements)

References 163 publications

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“…Lacking a clear mechanism for SMG1 inhibition to increase both ABCA1 expression and MVA synthesis genes, and with published studies supporting p53's non-canonical effects on lipid and cholesterol metabolisms [39,40], including the findings from the Prives' laboratory for a 'p53-ABCA1-SREBP2' metabolic axis [26], we asked if SMG1 knockdown effects on p53 isoform expression could explain any of our results. After demonstrating that SMG1 inhibition leads to an increase in p53 alternative splicing, we co-transfected MCF7 cells with SMG1 siRNA and the individual isoform-specific siRNAs and quantified ABCA1, SREBP2, and MVD mRNA levels.…”

Section: P53 Isoforms Modulate the Expression Of Abca1 Differently Wi...mentioning

confidence: 93%

A Novel Role of SMG1 in Cholesterol Homeostasis That Depends Partially on p53 Alternative Splicing

Philantrope

Diot

et al. 2022

Cancers

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SMG1, a phosphatidylinositol 3-kinase-related kinase (PIKK), essential in nonsense-mediated RNA decay (NMD), also regulates p53, including the alternative splicing of p53 isoforms reported to retain p53 functions. We confirm that SMG1 inhibition in MCF7 tumor cells induces p53β and show p53γ increase. Inhibiting SMG1, but not UPF1 (a core factor in NMD), upregulated several cholesterol pathway genes. SMG1 knockdown significantly increased ABCA1, a cholesterol efflux pump shown to be positively regulated by full-length p53 (p53α). An investigation of RASSF1C, an NMD target, increased following SMG1 inhibition and reported to inhibit miR-33a-5p, a canonical ABCA1-inhibiting miRNA, did not explain the ABCA1 results. ABCA1 upregulation following SMG1 knockdown was inhibited by p53β siRNA with greatest inhibition when p53α and p53β were jointly suppressed, while p53γ siRNA had no effect. In contrast, increased expression of MVD, a cholesterol synthesis gene upregulated in p53 deficient backgrounds, was sensitive to combined targeting of p53α and p53γ. Phenotypically, we observed increased intracellular cholesterol and enhanced sensitivity of MCF7 to growth inhibitory effects of cholesterol-lowering Fatostatin following SMG1 inhibition. Our results suggest deregulation of cholesterol pathway genes following SMG1 knockdown may involve alternative p53 programming, possibly resulting from differential effects of p53 isoforms on cholesterol gene expression.

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Section: P53 Isoforms Modulate the Expression Of Abca1 Differently Wi...mentioning

confidence: 93%

A Novel Role of SMG1 in Cholesterol Homeostasis That Depends Partially on p53 Alternative Splicing

Philantrope

Diot

et al. 2022

Cancers

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“…p53 regulates lipid metabolism. p53 is also involved in the transcription of genes associated with lipid metabolism through various mechanisms (6); it can bind directly to the promoter region of the transcription factor for sterol regulatory element-binding transcription factor 1 to inhibit its expression, which in turn regulates the expression of a group of genes involved in lipid metabolism (5). p53 also regulates the transcription of two enzymes involved in fatty acid oxidation, namely carnitine palmitoyl transferase 1C and phosphatidylate phosphatase, which regulates the transport of activated fatty acids to the mitochondria to enhance the oxidation of fatty acids in cells (5,85).…”

Section: P53-mediated Regulation Of Iron and Lipid Metabolism Involve...mentioning

confidence: 99%

Regulation of the p53‑mediated ferroptosis signaling pathway in cerebral ischemia stroke (Review)

Wang

2023

Exp Ther Med

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Stroke is one of the most threatening diseases worldwide, particularly in countries with larger populations; it is associated with high morbidity, mortality and disability rates. As a result, extensive research efforts are being made to address these issues. Stroke can include either hemorrhagic stroke (blood vessel ruptures) or ischemic stroke (blockage of an artery). Whilst the incidence of stroke is higher in the elderly population (≥65), it is also increasing in the younger population. Ischemic stroke accounts for ~85% of all stroke cases. The pathogenesis of cerebral ischemic injury can include inflammation, excitotoxic injury, mitochondrial dysfunction, oxidative stress, ion imbalance and increased vascular permeability. All of the aforementioned processes have been extensively studied, providing insights into the disease. Other clinical consequences observed include brain edema, nerve injury, inflammation, motor deficits and cognitive impairment, which not only cause disabilities obstructing daily life but also increase the mortality rates. Ferroptosis is a type of cell death that is characterized by iron accumulation and increased lipid peroxidation in cells. In particular, ferroptosis has been previously implicated in ischemia-reperfusion injury in the central nervous system. It has also been identified as a mechanism involved in cerebral ischemic injury. The tumor suppressor p53 has been reported to modulate the ferroptotic signaling pathway, which both positively and negatively affects the prognosis of cerebral ischemia injury. The present review summarizes the recent findings on the molecular mechanisms of ferroptosis under the regulation of p53 underlying cerebral ischemia injury. Understanding of the p53/ferroptosis signaling pathway may provide insights into developing methods for improving the diagnosis, treatment and even prevention of stroke. Contents1. Introduction 2. Potential pathogenesis and treatment status of cerebral ischemia injury 3. Ferroptosis 4. p53 5. p53-mediated regulation of iron and lipid metabolism involved in ferroptosis 6. p53-mediated ferroptosis 7. p53-mediated ferroptosis in the MCAO model 8. Conclusions and future perspectives

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“…In addition, iron plays dual roles in the CLL cells. On the one hand, iron is a critical cofactor that is required for DNA synthesis [ 80 ]. The transferrin receptor (TfR) contributes to iron import and a higher TfR concentration has been found in CLL directly reflecting the large tumor burden [ 81 ].…”

Section: Intracelluar Metabolismmentioning

confidence: 99%

Targeting metabolic reprogramming in chronic lymphocytic leukemia

Nie

Yun

et al. 2022

Exp Hematol Oncol

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Metabolic reprogramming, fundamentally pivotal in carcinogenesis and progression of cancer, is considered as a promising therapeutic target against tumors. In chronic lymphocytic leukemia (CLL) cells, metabolic abnormalities mediate alternations in proliferation and survival compared with normal B cells. However, the role of metabolic reprogramming is still under investigation in CLL. In this review, the critical metabolic processes of CLL were summarized, particularly glycolysis, lipid metabolism and oxidative phosphorylation. The effects of T cells and stromal cells in the microenvironment on metabolism of CLL were also elucidated. Besides, the metabolic alternation is regulated by some oncogenes and tumor suppressor regulators, especially TP53, MYC and ATM. Thus, the agents targeting metabolic enzymes or signal pathways may impede the progression of CLL. Both the inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR) statins and the lipoprotein lipase inhibitor orlistat induce the apoptosis of CLL cells. In addition, a series of oxidative phosphorylation inhibitors play important roles in decreasing the proliferation of CLL cells. We epitomized recent advancements in metabolic reprogramming in CLL and discussed their clinical potentiality for innovative therapy options. Metabolic reprogramming plays a vital role in the initiation and progression of CLL. Therapeutic approaches targeting metabolism have their advantages in improving the survival of CLL patients. This review may shed novel light on the metabolism of CLL, leading to the development of targeted agents based on the reshaping metabolism of CLL cells.

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The p53 Family: A Role in Lipid and Iron Metabolism

Cited by 20 publications

References 163 publications

A Novel Role of SMG1 in Cholesterol Homeostasis That Depends Partially on p53 Alternative Splicing

A Novel Role of SMG1 in Cholesterol Homeostasis That Depends Partially on p53 Alternative Splicing

Regulation of the p53‑mediated ferroptosis signaling pathway in cerebral ischemia stroke (Review)

Targeting metabolic reprogramming in chronic lymphocytic leukemia

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