The p53 Tumor Suppressor and Copper Metabolism: An Unrevealed but Important Link

Tsymbal, Sergey A.; Refeld, A. G.; Kuchur, O. A.

doi:10.1134/s0026893322060188

Cited by 8 publications

(3 citation statements)

References 108 publications

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“…In recent years, p53 has been shown to have an essential effect on cuproptosis regulation [ 64 ]. Researchers have recorded significantly increased ATOX1 levels in p53-inactivated cells, suggesting that p53 is a negative regulator of ATOX1, and that regulation of p53 expression is crucial for intracellular Cu + transport [ 65 , 66 ]. In addition to blunting glycolysis and promoting metabolism in the TCA cycle [ 67 ], p53 may also have notable effects on other pathways involved in cuproptosis, including increasing the instability of Fe–S clusters and reducing the production of GSH.…”

Section: Cuproptosis In Dmmentioning

confidence: 99%

The Molecular Mechanisms of Cuproptosis and Small-Molecule Drug Design in Diabetes Mellitus

Pan,

Huang,

Gan

et al. 2024

Molecules

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In the field of human health research, the homeostasis of copper (Cu) is receiving increased attention due to its connection to pathological conditions, including diabetes mellitus (DM). Recent studies have demonstrated that proteins associated with Cu homeostasis, such as ATOX1, FDX1, ATP7A, ATPB, SLC31A1, p53, and UPS, also contribute to DM. Cuproptosis, characterized by Cu homeostasis dysregulation and Cu overload, has been found to cause the oligomerization of lipoylated proteins in mitochondria, loss of iron–sulfur protein, depletion of glutathione, production of reactive oxygen species, and cell death. Further research into how cuproptosis affects DM is essential to uncover its mechanism of action and identify effective interventions. In this article, we review the molecular mechanism of Cu homeostasis and the role of cuproptosis in the pathogenesis of DM. The study of small-molecule drugs that affect these proteins offers the possibility of moving from symptomatic treatment to treating the underlying causes of DM.

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Section: Cuproptosis In Dmmentioning

confidence: 99%

The Molecular Mechanisms of Cuproptosis and Small-Molecule Drug Design in Diabetes Mellitus

Pan,

Huang,

Gan

et al. 2024

Molecules

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“…Along with the regulation of the cell cycle and responses to DNA damage, p53 is a modulator of metabolic cascades. The role of p53 in controlling the expression of genes for glucose metabolism [19,20], respiration [21], and metabolism of transition metals, especially copper [22][23][24], is known. The connection of p53 with copper metabolism is also important due to the discovery of the role of this metal in tumor biology [25][26][27][28].…”

Section: Introductionmentioning

confidence: 99%

Atox1-Cyclin D1 Loop Activity is Critical for Survival of Tumor Cells with Inactivated TP53

Kuchur,

Pogodaeva,

Shcherbakova

et al. 2024

Preprint

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The search for relevant molecular targets is one of the main tasks of modern tumor chemotherapy. To successfully achieve this, it is necessary to have the most complete understanding of the functioning of the cell's transcriptional apparatus, particularly related to proliferation. The p53 protein plays an important role in regulating processes such as apoptosis, repair, and cell division, and the loss of its functionality often accompanies various types of tumors and contributes to the development of chemoresistance. Additionally, the proliferative activity of tumor cells is closely related to the metabolism of transition metals. For example, the metallochaperone Atox1, a copper transporter protein, acts as a transcription activator for cyclin D1, promoting progression through the G1/S phase of the cell cycle. On the other hand, p53 suppresses cyclin D1 at the transcriptional level, thereby these proteins have divergent effects on cell cycle progression. However, the contribution of the interaction between these proteins to cell survival is poorly understood. This work demonstrates that there not only exists a positive feedback loop between Atox1 and cyclin D1, but also that the activity of this loop depends on the status of the TP53 gene. Upon inactivation of TP53 in A549 and HepG2 cell lines, the expression of ATOX1 and CCND1 genes is enhanced, and their suppression in these cells leads to pronounced apoptosis. This fundamental observation may be useful in selecting more precise interventions for combined therapy of p53-negative tumors.

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“…Furthermore, the balance of redox reactions in the cell is closely linked to the regulation of intracellular homeostasis of transition metals such as zinc (Zn), iron (Fe), and copper (Cu) [5][6][7][8][9][10]. However, there is limited information available regarding the correlation or codependence between the expression levels of p53 and proteins involved in metal metabolism in tumors [11][12][13][14]. Given the unique properties of copper and copper-binding proteins, investigating the metabolism of this metal becomes particularly attractive for developing approaches to combined tumor therapy [15,16].…”

Section: Introductionmentioning

confidence: 99%

The p53 protein is a suppressor of Atox1 copper chaperon in tumor cells under genotoxic effects

Tsymbal,

Refeld,

Zatsepin

et al. 2023

PLoS ONE

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The p53 protein is crucial for regulating cell survival and apoptosis in response to DNA damage. However, its influence on therapy effectiveness is controversial: when DNA damage is high p53 directs cells toward apoptosis, while under moderate genotoxic stress it saves the cells from death and promote DNA repair. Furthermore, these processes are influenced by the metabolism of transition metals, particularly copper since they serve as cofactors for critical enzymes. The metallochaperone Atox1 is under intensive study in this context because it serves as transcription factor allegedly mediating described effects of copper. Investigating the interaction between p53 and Atox1 could provide insights into tumor cell survival and potential therapeutic applications in oncology. This study explores the relationship between p53 and Atox1 in HCT116 and A549 cell lines with wild type and knockout TP53. The study found an inverse correlation between Atox1 and p53 at the transcriptional and translational levels in response to genotoxic stress. Atox1 expression decreased with increased p53 activity, while cells with inactive p53 had significantly higher levels of Atox1. Suppression of both genes increased apoptosis, while suppression of the ATOX1 gene prevented apoptosis even under the treatment with chemotherapeutic drugs. The findings suggest that Atox1 may act as one of key elements in promotion of cell cycle under DNA-damaging conditions, while p53 works as an antagonist by inhibiting Atox1. Understanding of this relationship could help identify potential targets in cell signaling pathways to enhance the effectiveness of combined antitumor therapy, especially in tumors with mutant or inactive p53.

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The p53 Tumor Suppressor and Copper Metabolism: An Unrevealed but Important Link

Cited by 8 publications

References 108 publications

The Molecular Mechanisms of Cuproptosis and Small-Molecule Drug Design in Diabetes Mellitus

The Molecular Mechanisms of Cuproptosis and Small-Molecule Drug Design in Diabetes Mellitus

Atox1-Cyclin D1 Loop Activity is Critical for Survival of Tumor Cells with Inactivated TP53

The p53 protein is a suppressor of Atox1 copper chaperon in tumor cells under genotoxic effects

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