African-centric TP53 variant increases iron accumulation and bacterial pathogenesis but improves response to malaria toxin

Singh, Kumar Sachin; Leu, Julia I-Ju; Barnoud, Thibaut; Vonteddu, Prashanthi; Gnanapradeepan, Keerthana; Lin, Cindy; Liu, Qin; Barton, James C.; Kossenkov, Andrew V.; George, Donna L.; Murphy, Maureen E.; Dotiwala, Farokh

doi:10.1038/s41467-019-14151-9

Cited by 36 publications

(38 citation statements)

References 66 publications

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“…132 In turn, the resulting ferroptosis deficiency causes iron to accumulate in P47S macrophages, increasing the risk of bacterial infection. 133 MDM2 ubiquitinates TP53 for proteasomal degradation. Podocyte-specific MDM2-knockout mice develop TP53-mediated kidney injury through the activation of a mixed type of cell death, including ferroptosis.…”

Section: Tp53mentioning

confidence: 99%

Ferroptosis: molecular mechanisms and health implications

et al. 2020

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Cell death can be executed through different subroutines. Since the description of ferroptosis as an iron-dependent form of non-apoptotic cell death in 2012, there has been mounting interest in the process and function of ferroptosis. Ferroptosis can occur through two major pathways, the extrinsic or transporter-dependent pathway and the intrinsic or enzyme-regulated pathway. Ferroptosis is caused by a redox imbalance between the production of oxidants and antioxidants, which is driven by the abnormal expression and activity of multiple redox-active enzymes that produce or detoxify free radicals and lipid oxidation products. Accordingly, ferroptosis is precisely regulated at multiple levels, including epigenetic, transcriptional, posttranscriptional and posttranslational layers. The transcription factor NFE2L2 plays a central role in upregulating anti-ferroptotic defense, whereas selective autophagy may promote ferroptotic death. Here, we review current knowledge on the integrated molecular machinery of ferroptosis and describe how dysregulated ferroptosis is involved in cancer, neurodegeneration, tissue injury, inflammation, and infection.

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Section: Tp53mentioning

confidence: 99%

Ferroptosis: molecular mechanisms and health implications

et al. 2020

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“…S47 mice display more productive intracellular bacterial infections but are protective against malarial toxin hemozoin. Furthermore, iron chelators and LXR agonists can improve the response of S47 mice to bacterial infection [129]. These results suggest that p53-mediated ferroptosis plays an important role in regulation of iron accumulation to modulate macrophage functions and host immune responses [129].…”

Section: Ferroptosis Regulated By Mutp53 P53 Variants and P53 Familymentioning

confidence: 99%

“…The S47 p53 variant shows an impaired ability to transcriptionally induce a subset of p53 target genes, including two well-known genes involved in metabolism, GLS2 and SCO2, suggesting that the defect in metabolic regulation may contribute to the reduced ferroptosis and the tumor-prone phenotype observed in S47 mice [127]. Notably, further studies showed that the ferroptotic defect in S47 p53 variant results in iron accumulation in macrophages, which alters macrophage cytokine profiles and leads to the higher level and activity of arginase and decreased activity of nitric oxide synthase [129]. S47 macrophages have decreased liver X receptor (LXR) activation, inflammation and antibacterial defense.…”

Section: Ferroptosis Regulated By Mutp53 P53 Variants and P53 Familymentioning

confidence: 99%

“…It is possible that p53 is involved in these processes in a tissue-and stress-dependent manner through promoting or inhibiting ferroptosis. It is worth noting that p53-regulated ferroptosis has been shown to play an important role in differentially regulating host immune responses to bacterial and malarial infections through modulating macrophage functions [129]. While many studies on the regulation of ferroptosis by p53 have focused on the tumor suppressive function of p53, it is crucial to determine the contribution of ferroptosis to the role of p53 in metabolism, immune response, neurodegeneration and tissue ischemia/reperfusion injuries.…”

Section: Summary and Perspectivesmentioning

confidence: 99%

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The Regulation of Ferroptosis by Tumor Suppressor p53 and its Pathway

Liu

Zhang

Wang

et al. 2020

IJMS

156

124

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Tumor suppressor p53 plays a key role in tumor suppression. In addition to tumor suppression, p53 is also involved in many other biological and pathological processes, such as immune response, maternal reproduction, tissue ischemia/reperfusion injuries and neurodegenerative diseases. While it has been widely accepted that the role of p53 in regulation of cell cycle arrest, senescence and apoptosis contributes greatly to the function of p53 in tumor suppression, emerging evidence has implicated that p53 also exerts its tumor suppressive function through regulation of many other cellular processes, such as metabolism, anti-oxidant defense and ferroptosis. Ferroptosis is a unique iron-dependent form of programmed cell death driven by lipid peroxidation in cells. Ferroptosis has been reported to be involved in cancer, tissue ischemia/reperfusion injuries and neurodegenerative diseases. Recent studies have shown that ferroptosis can be regulated by p53 and its signaling pathway as well as tumor-associated mutant p53. Interestingly, the regulation of ferroptosis by p53 appears to be highly context-dependent. In this review, we summarize recent advances in the regulation of ferroptosis by p53 and its signaling pathway. Further elucidation of the role and molecular mechanism of p53 in ferroptosis regulation will yield new therapeutic strategies for cancer and other diseases, including neurodegenerative diseases and tissue ischemia/reperfusion injuries.

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“…Noteworthily, these ferroptotic defects cause iron accumulation and lead toward the differentiation of anti-inflammatory macrophages. The altered immune profiles allow more productive protection of intracellular bacterial infections against malarial toxin hemozoin [ 84 ]. Therefore, ferroptosis also plays a role in the elimination of iron-accumulated macrophages and the shaping of host immune responses [ 84 ].…”

Section: The Involvement Of Various Ddr Components In Ferroptosismentioning

confidence: 99%

The Intersection of DNA Damage Response and Ferroptosis—A Rationale for Combination Therapeutics

Chen

Tseng

Chi

2020

Biology

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Ferroptosis is a novel form of iron-dependent cell death characterized by lipid peroxidation. While the importance and disease relevance of ferroptosis are gaining recognition, much remains unknown about its interaction with other biological processes and pathways. Recently, several studies have identified intricate and complicated interplay between ferroptosis, ionizing radiation (IR), ATM (ataxia–telangiectasia mutated)/ATR (ATM and Rad3-related), and tumor suppressor p53, which signifies the participation of the DNA damage response (DDR) in iron-related cell death. DDR is an evolutionarily conserved response triggered by various DNA insults to attenuate proliferation, enable DNA repairs, and dispose of cells with damaged DNA to maintain genome integrity. Deficiency in proper DDR in many genetic disorders or tumors also highlights the importance of this pathway. In this review, we will focus on the biological crosstalk between DDR and ferroptosis, which is mediated mostly via noncanonical mechanisms. For clinical applications, we also discuss the potential of combining ionizing radiation and ferroptosis-inducers for synergistic effects. At last, various ATM/ATR inhibitors under clinical development may protect ferroptosis and treat many ferroptosis-related diseases to prevent cell death, delay disease progression, and improve clinical outcomes.

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African-centric TP53 variant increases iron accumulation and bacterial pathogenesis but improves response to malaria toxin

Cited by 36 publications

References 66 publications

Ferroptosis: molecular mechanisms and health implications

Ferroptosis: molecular mechanisms and health implications

The Regulation of Ferroptosis by Tumor Suppressor p53 and its Pathway

The Intersection of DNA Damage Response and Ferroptosis—A Rationale for Combination Therapeutics

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