Role of p53 in Regulating Radiation Responses

Okazaki, Ryo

doi:10.3390/life12071099

Cited by 14 publications

(11 citation statements)

References 204 publications

(217 reference statements)

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“…Nodes with a high degree, also known as hubs, are more likely to play an essential role (He and Zhang, 2006). In line with this, multiple review articles have described the key role of MDM2 in the p53-MDM2-signaling axis as part of the DDR (Nag et al, 2013;Haronikova et al, 2019;Gnanasundram et al, 2021;Okazaki, 2022). In addition, we found that MDM2 is targeted by 44 different miRNAs.…”

Section: Figuresupporting

confidence: 76%

A workflow for the creation of regulatory networks integrating miRNAs and lncRNAs associated with exposure to ionizing radiation using open source data and tools

Freiesleben

Unverricht-Yeboah²,

Gütebier³

et al. 2022

Front. Syst. Biol.

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MicroRNAs (miRNAs) and long non-coding RNAs (lncRNAs) are involved in the modulation of the DNA-damage response (DDR) and upon exposure to ionizing radiation (IR), their expression fluctuates. In this study, we propose a workflow that enables the creation of regulatory networks by integrating transcriptomics data as well as regulatory data in order to better understand the interplay between genes, transcription factors (TFs), miRNAs, and lncRNAs in the cellular response to IR. We preprocessed and analyzed publicly available gene expression profiles and then applied our consensus and integration approach using open source data and tools. To exemplify the benefits of our proposed workflow, we identified a total of 32 differentially expressed transcripts corresponding to 20 unique differentially expressed genes (DEGs) and using these DEGs, we constructed a regulatory network consisting of 106 interactions and 100 nodes (11 DEGs, 78 miRNAs, 1 DEG acting as a TF, and 10 lncRNAs). Overrepresentation analyses (ORAs) furthermore linked our DEGs and miRNAs to annotations pertaining to the DDR and to IR. Our results show that MDM2 and E2F7 function as network hubs, and E2F7, miR-25-3p, let-7a-5p, and miR-497-5p are the four nodes with the highest betweenness centrality. In brief, our workflow, that is based on open source data and tools, and that generates a regulatory network, provides novel insights into the regulatory mechanisms involving miRNAs and lncRNAs in the cellular response to IR.

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Section: Figuresupporting

confidence: 76%

A workflow for the creation of regulatory networks integrating miRNAs and lncRNAs associated with exposure to ionizing radiation using open source data and tools

Freiesleben

Unverricht-Yeboah²,

Gütebier³

et al. 2022

Front. Syst. Biol.

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“…In cells, the phosphorylation of H2AX at its serine 139 residue (rH2AX) and the activation of p53 are crucial responses to DNA damage caused by radiation, particularly double-strand breaks [ 62 , 63 , 64 ]. These responses aid in the repair of damaged DNA or remove cells with significant damage through apoptosis [ 62 , 63 , 64 ].…”

Section: Resultsmentioning

confidence: 99%

Dose-Dependent Effects of Radiation on Mitochondrial Morphology and Clonogenic Cell Survival in Human Microvascular Endothelial Cells

Wang,

Rivas,

Wilson

et al. 2023

Cells

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To better understand radiation-induced organ dysfunction at both high and low doses, it is critical to understand how endothelial cells (ECs) respond to radiation. The impact of irradiation (IR) on ECs varies depending on the dose administered. High doses can directly damage ECs, leading to EC impairment. In contrast, the effects of low doses on ECs are subtle but more complex. Low doses in this study refer to radiation exposure levels that are below those that cause immediate and necrotic damage. Mitochondria are the primary cellular components affected by IR, and this study explored their role in determining the effect of radiation on microvascular endothelial cells. Human dermal microvascular ECs (HMEC-1) were exposed to varying IR doses ranging from 0.1 Gy to 8 Gy (~0.4 Gy/min) in the AFRRI 60-Cobalt facility. Results indicated that high doses led to a dose-dependent reduction in cell survival, which can be attributed to factors such as DNA damage, oxidative stress, cell senescence, and mitochondrial dysfunction. However, low doses induced a small but significant increase in cell survival, and this was achieved without detectable DNA damage, oxidative stress, cell senescence, or mitochondrial dysfunction in HMEC-1. Moreover, the mitochondrial morphology was assessed, revealing that all doses increased the percentage of elongated mitochondria, with low doses (0.25 Gy and 0.5 Gy) having a greater effect than high doses. However, only high doses caused an increase in mitochondrial fragmentation/swelling. The study further revealed that low doses induced mitochondrial elongation, likely via an increase in mitochondrial fusion protein 1 (Mfn1), while high doses caused mitochondrial fragmentation via a decrease in optic atrophy protein 1 (Opa1). In conclusion, the study suggests, for the first time, that changes in mitochondrial morphology are likely involved in the mechanism for the radiation dose-dependent effect on the survival of microvascular endothelial cells. This research, by delineating the specific mechanisms through which radiation affects endothelial cells, offers invaluable insights into the potential impact of radiation exposure on cardiovascular health.

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“…Genetic instability is one of the most striking features of malignant tumours, however, P53 plays an important role for detecting DNA damage and repairing the genome. When p53 responds to DNA damage, it triggers either cell cycle arrest or apoptosis (Okazaki, 2022). Radiotherapy destroys cancer cells via DNA damage; DNA damage is causing increase in p53 expression via ATM kinase activation (Cui et al, 2022).…”

Section: Discussionmentioning

confidence: 99%

Phosphorylated P53 (TP53) in Cancer Patients Undergoing Radiotherapy

2023

JPRD

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Introduction: Cancer is a common disease worldwide, and radiotherapy is an important option for cancer treatment. P53 tumour suppressor has a role in apoptosis and cancer treatment response. P53 is phosphorylated in response to ionizing radiation by kinases of the ataxia telangiectasia mutation family (ATM). The aim of this study was to detect the DND damage response in cancer patients before and after radiation therapy through measurements the expression levels of phosphorylated P53 on T18. Material and Methods: Total of 28 cancer patients on radiotherapy were participate in this study to collect blood samples pre and post radiotherapy compared to 28 healthy people matched in age and sex as control group. P53 antibody used against Phospho-p53 (T18) was obtained from CUSABIO using enzyme linked immunosorbent assay (ELISA). Results: 21 of patients were breast cancer, and 7 of patients were Head and Neck. 6 male and 22 female. Median of age was 44 years old. Median of body mass index (BMI) for breast cancer patients was 30 while BMI for head and neck was 23. The absorbed dose for breast cancer was 40.5Gy. While the doses for Head and neck cancers were between 20Gy- 66Gy. Phosphorylated P53 expression increased significantly (P= <0.0001) in the patients preradiotherapy compared to the control group. While no significant difference observed between preradiotherapy and postradiotherapy groups (P=0.7). Individually, 19 patients showed increased in phosphorylated P53 expression postradiotherapy, while, nine patients were showed low P53 postradiotherapy, 8 of them diagnosed with breast cancer and 1 diagnosed with Oesophagus. Conclusion: phosphorylated on T18 can be consider a predictive marker for cancer. Phosphorylated P53 can be indict the DNA damage and response through its activation and proapoptotic effects. Protein expression such as P53 can be use as biomarker to demonstrate individual radiation sensitivity in cancer patients.

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Role of p53 in Regulating Radiation Responses

Cited by 14 publications

References 204 publications

A workflow for the creation of regulatory networks integrating miRNAs and lncRNAs associated with exposure to ionizing radiation using open source data and tools

A workflow for the creation of regulatory networks integrating miRNAs and lncRNAs associated with exposure to ionizing radiation using open source data and tools

Dose-Dependent Effects of Radiation on Mitochondrial Morphology and Clonogenic Cell Survival in Human Microvascular Endothelial Cells

Phosphorylated P53 (TP53) in Cancer Patients Undergoing Radiotherapy

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