Context is key: Understanding the regulation, functional control, and activities of the p53 tumour suppressor

Moxley, Anne Hucks; Reisman, David

doi:10.1002/cbf.3590

Cited by 18 publications

(15 citation statements)

References 173 publications

(255 reference statements)

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“…MDA-MB-231 cells bear the R280K mutation in the p53 DNA-binding domain, which renders p53 defective in transcription activation [ 74 , 75 ], leading to an impairment in G1 arrest [ 76 , 77 ]. The impact of p53 activity on the efficacy of RAD51i is of significant interest, because approximately 50% of all cancers carry p53 mutations [ 78 ]. Recently, it was shown that p53 may either promote or antagonize the anti-proliferating effect of B02 alone or in combination with topotecan in retinoblastoma cells depending on whether the BAX (apoptotic) or p21 (G1 cell cycle arrest) pathways predominate in these cells [ 79 ].…”

Section: Discussionmentioning

confidence: 99%

New RAD51 Inhibitors to Target Homologous Recombination in Human Cells

Shkundina

Gall²,

Dick

et al. 2021

Genes

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Targeting DNA repair proteins with small-molecule inhibitors became a proven anti-cancer strategy. Previously, we identified an inhibitor of a major protein of homologous recombination (HR) RAD51, named B02. B02 inhibited HR in human cells and sensitized them to chemotherapeutic drugs in vitro and in vivo. Here, using a medicinal chemistry approach, we aimed to improve the potency of B02. We identified the B02 analog, B02-isomer, which inhibits HR in human cells with significantly higher efficiency. We also show that B02-iso sensitizes triple-negative breast cancer MDA-MB-231 cells to the PARP inhibitor (PARPi) olaparib.

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Section: Discussionmentioning

confidence: 99%

New RAD51 Inhibitors to Target Homologous Recombination in Human Cells

Shkundina

Gall²,

Dick

et al. 2021

Genes

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“…There are some limitations of the current study. As is well known, p53 protein has a very complex network of activity [ 50 ]. In the study, we did not provide a mechanistic interpretation of how p53, MDM2, and miR-29a interact, especially regarding the crosstalk between the status of p53 (wild-type vs mutated) and miR-29a.…”

Section: Discussionmentioning

confidence: 99%

miR-29a sensitizes the response of glioma cells to temozolomide by modulating the P53/MDM2 feedback loop

et al. 2021

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Recently, pivotal functions of miRNAs in regulating common tumorigenic processes and manipulating signaling pathways in brain tumors have been recognized; notably, miR‐29a is closely associated with p53 signaling, contributing to the development of glioma. However, the molecular mechanism of the interaction between miR-29a and p53 signaling is still to be revealed. Herein, a total of 30 glioma tissues and 10 non-cancerous tissues were used to investigate the expression of miR‐29a. CCK-8 assay and Transwell assay were applied to identify the effects of miR-29a altered expression on the malignant biological behaviors of glioma cells in vitro, including proliferation, apoptosis, migration and invasion. A dual-luciferase reporter assay was used to further validate the regulatory effect of p53 or miR-29a on miR-29a or MDM2, respectively, at the transcriptional level. The results showed that miR-29a expression negatively correlated with tumor grade of human gliomas; at the same time it inhibited cell proliferation, migration, and invasion and promoted apoptosis of glioma cells in vitro. Mechanistically, miR-29a expression was induced by p53, leading to aberrant expression of MDM2 targeted by miR-29a, and finally imbalanced the activity of the p53-miR-29a-MDM2 feedback loop. Moreover, miR-29a regulating p53/MDM2 signaling sensitized the response of glioma cells to temozolomide treatment. Altogether, the study demonstrated a potential molecular mechanism in the tumorigenesis of glioma, while offering a possible target for treating human glioma in the future.

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“…It is a sequence-specific transcription factor that is a critical regulator of tumor suppression caused due to genomic instability. [41] Under normal conditions, p53 levels are maintained low, and its expression is induced upon DNA damage F I G U R E 1 Regulation of p53 mRNA translation and stability upon genotoxic stress. In addition to regulation of p53 protein level by p53-MDM2 axis, multiple proteins such as NCL, PTB, MDM2, and RPL26 regulate p53 protein levels by affecting mRNA translation and/or stability.…”

Section: P53 Mrna Regulation Is Mediated By Multiple Rbpsmentioning

confidence: 99%

Genotoxic stress response: What is the role of cytoplasmic mRNA fate?

2021

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Genotoxic stress leads to DNA damage which can be detrimental to the cell. A wellorchestrated cellular response is mounted to manage and repair the genotoxic stressinduced DNA damage. Our understanding of genotoxic stress response is derived mainly from studies focused on transcription, mRNA splicing, and protein turnover. Surprisingly not as much is understood about the role of mRNA translation and decay in genotoxic stress response. This is despite the fact that regulation of gene expression at the level of mRNA translation and decay plays a critical role in a myriad of cellular processes. This review aims to summarize some of the known findings of the role of mRNA translation and decay by focusing on two categories of examples. We discuss examples of mRNA whose fates are regulated in the cytoplasm and RNA-binding proteins that regulate mRNA fates in response to genotoxic stress.

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Context is key: Understanding the regulation, functional control, and activities of the p53 tumour suppressor

Cited by 18 publications

References 173 publications

New RAD51 Inhibitors to Target Homologous Recombination in Human Cells

New RAD51 Inhibitors to Target Homologous Recombination in Human Cells

miR-29a sensitizes the response of glioma cells to temozolomide by modulating the P53/MDM2 feedback loop

Genotoxic stress response: What is the role of cytoplasmic mRNA fate?

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