Mechanisms of Ferroptosis and Relations With Regulated Cell Death: A Review

Frontiers in Physiology, Journal Year: 2019, Volume and Issue: 10

Published: Feb. 26, 2019

Ferroptosis is a newly identified form of nonapoptotic regulated cell death (RCD) characterized by iron-dependent accumulation lipid peroxides. It morphologically and biochemically different from known types death. plays vital role in the treatment tumors, renal failure ischemia reperfusion injury (IRI). Inhibition glutathione peroxidase 4 (GPX4), starvation cysteine peroxidation arachidonoyl (AA) trigger ferroptosis cells. Iron chelators, lipophilic antioxidants specific inhibitor prevent ferroptosis. Although massive researches have demonstrated importance human, its mechanism not really clear. In this review, we get out mess dividing processes that induce into two aspects: facilitate formation peroxides suppress reduction At same time, summarize relations between several

Language: Английский

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Therapeutic targeting of p53: all mutants are equal, but some mutants are more equal than others

Nature Reviews Clinical Oncology, Journal Year: 2017, Volume and Issue: 15(1), P. 13 - 30

Published: Sept. 26, 2017

Language: Английский

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Genomic characterization of metastatic patterns from prospective clinical sequencing of 25,000 patients

Cell, Journal Year: 2022, Volume and Issue: 185(3), P. 563 - 575.e11

Published: Feb. 1, 2022

Language: Английский

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An evolutionary perspective on field cancerization

Nature reviews. Cancer, Journal Year: 2017, Volume and Issue: 18(1), P. 19 - 32

Published: Dec. 8, 2017

Language: Английский

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Targeting p53 pathways: mechanisms, structures and advances in therapy

Signal Transduction and Targeted Therapy, Journal Year: 2023, Volume and Issue: 8(1)

Published: March 1, 2023

The TP53 tumor suppressor is the most frequently altered gene in human cancers, and has been a major focus of oncology research. p53 protein transcription factor that can activate expression multiple target genes plays critical roles regulating cell cycle, apoptosis, genomic stability, widely regarded as "guardian genome". Accumulating evidence shown also regulates metabolism, ferroptosis, microenvironment, autophagy so on, all which contribute to suppression. Mutations not only impair its function, but confer oncogenic properties mutants. Since mutated inactivated malignant tumors, it very attractive for developing new anti-cancer drugs. However, until recently, was considered an "undruggable" little progress made with p53-targeted therapies. Here, we provide systematic review diverse molecular mechanisms signaling pathway how mutations impact progression. We discuss key structural features inactivation by mutations. In addition, efforts have therapies, challenges encountered clinical development.

Language: Английский

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Mechanisms of transcriptional regulation by p53

Cell Death and Differentiation, Journal Year: 2017, Volume and Issue: 25(1), P. 133 - 143

Published: Nov. 10, 2017

p53 is a transcription factor that suppresses tumor growth through regulation of dozens target genes with diverse biological functions. The activity this master inactivated in nearly all tumors, either by mutations the TP53 locus or oncogenic events decrease wild-type protein, such as overexpression repressor MDM2. However, despite decades intensive research, our collective understanding signaling cascade remains incomplete. In review, we focus on recent advances mechanisms p53-dependent transcriptional control they relate to five key areas: (1) functionally distinct N-terminal transactivation domains, (2) regulatory roles its C-terminal domain, (3) evidence solely direct activator, not repressor, (4) ability recognize many enhancers across chromatin environments, and (5) modify program context-dependent manner.

Language: Английский

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Perspective on Oncogenic Processes at the End of the Beginning of Cancer Genomics

Cell, Journal Year: 2018, Volume and Issue: 173(2), P. 305 - 320.e10

Published: April 1, 2018

Highlights•An overview of PanCancer Atlas analyses on oncogenic molecular processes•Germline genome affects somatic genomic landscape in a pathway-dependent fashion•Genome mutations impact expression, signaling, and multi-omic profiles•Mutation burdens drivers influence immune-cell composition microenvironmentSummaryThe Cancer Genome (TCGA) has catalyzed systematic characterization diverse alterations underlying human cancers. At this historic junction marking the completion over 11,000 tumors from 33 cancer types, we present our current understanding processes governing oncogenesis. We illustrate insights into through synthesis findings TCGA project three facets oncogenesis: (1) driver mutations, germline pathogenic variants, their interactions tumor; (2) tumor epigenome transcriptome proteome; (3) relationship between microenvironment, including implications for drugs targeting events immunotherapies. These results will anchor future rare common primary relapsed tumors, cancers across ancestry groups guide deployment clinical sequencing.Graphical abstract

Language: Английский

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The p53 Pathway in Glioblastoma

Cancers, Journal Year: 2018, Volume and Issue: 10(9), P. 297 - 297

Published: Sept. 1, 2018

The tumor suppressor and transcription factor p53 plays critical roles in prevention by orchestrating a wide variety of cellular responses, including damaged cell apoptosis, maintenance genomic stability, inhibition angiogenesis, regulation metabolism microenvironment. TP53 is one the most commonly deregulated genes cancer. p53-ARF-MDM2 pathway 84% glioblastoma (GBM) patients 94% GBM lines. Deregulated components have been implicated invasion, migration, proliferation, evasion cancer stemness. These are also regulated various microRNAs long non-coding RNAs. mutations mostly point that lead to high expression gain function (GOF) oncogenic variants protein. relatively understudied GOF mutants promote malignancy, possibly acting as factors on set other than those wild type p53. Their correlates with worse prognosis, highlighting their potential importance markers targets for therapy. Understanding mutant functions led development novel approaches restore activity or degradation future therapies.

Language: Английский

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Mutant p53 as a target for cancer treatment

European Journal of Cancer, Journal Year: 2017, Volume and Issue: 83, P. 258 - 265

Published: July 27, 2017

Language: Английский

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Optimized p53 immunohistochemistry is an accurate predictor of TP53 mutation in ovarian carcinoma

The Journal of Pathology Clinical Research, Journal Year: 2016, Volume and Issue: 2(4), P. 247 - 258

Published: June 9, 2016

Abstract TP53 mutations are ubiquitous in high‐grade serous ovarian carcinomas (HGSOC), and the presence of mutation discriminates between high low‐grade is now an important biomarker for clinical trials targeting mutant p53. p53 immunohistochemistry (IHC) widely used as a surrogate but its accuracy has not been established. The objective this study was to test whether improved methods IHC could reliably predict independently identified by next generation sequencing (NGS). Four assays tagged‐amplicon NGS were performed on 171 HGSOC 80 endometrioid (EC). expression scored overexpression (OE), complete absence (CA), cytoplasmic (CY) or wild type (WT). evaluated binary classifier where any abnormal staining predicted deleterious ternary OE, CA WT gain‐of‐function (GOF nonsynonymous), loss‐of‐function (LOF including stopgain, indel, splicing) no detectable (NDM), respectively. Deleterious detected 169/171 (99%) 7/80 (8.8%) EC. overall best performing assay prediction 0.94 0.91 respectively, which 0.97 (sensitivity 0.96, specificity 1.00) 0.95 after secondary analysis discordant cases. sensitivity predicting LOF lower at 0.76 because protein 13 with mutations. CY associated seen 4 (2.3%) HGSOC. Optimized can approach 100% negative predictive value clinically useful it exclude possibility tumour. 4.1% cases have while harboring mutation, limits 96%.

Language: Английский

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