XPC multifaceted roles beyond DNA damage repair: p53-dependent and p53-independent functions of XPC in cell fate decisions

Zebian, Abir; El-Dor, Maya; Shaito, Abdullah; Mazurier, Frédéric; Rezvani, Hamid Reza; Zibara, Kazem

doi:10.1016/j.mrrev.2021.108400

Cited by 6 publications

(2 citation statements)

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“… 52 The interaction of these proteins with effector proteins may lead to various cell fates, such as apoptosis, senescence or tumorigenesis. 53 , 54 …”

Section: Introductionmentioning

confidence: 99%

Targeting p53 pathways: mechanisms, structures and advances in therapy

Wang

Guo

Wei

et al. 2023

Sig Transduct Target Ther

238

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

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“… 52 The interaction of these proteins with effector proteins may lead to various cell fates, such as apoptosis, senescence or tumorigenesis. 53 , 54 …”

Section: Introductionmentioning

confidence: 99%

Targeting p53 pathways: mechanisms, structures and advances in therapy

Wang

Guo

Wei

et al. 2023

Sig Transduct Target Ther

238

View full text Add to dashboard Cite

show abstract

“…Structurally, the p53 protein comprises four major functional domains: the N-terminal transactivation domain (TAD), the proline-rich domain (PRD), the DNA-binding domain (DBD), which is often the focus of mutations, and the unstructured C-terminal domain (CTD) including a nuclear localization signal (NLS) and a nuclear export signal (NES) 6 . As a regulator of gene expression, p53 governs cellular responses under stress conditions, activating mechanisms such as cell cycle arrest, apoptosis, and senescence 7 . Mutations in TP53 are known to disrupt normal functioning of p53, leading to loss of its tumor-suppressive activities and contributing to the development and progression of malignancies.…”

Section: Introductionmentioning

confidence: 99%

Correlating p53 immunostaining patterns with somatic TP53 mutation and functional properties of mutant p53 in triple-negative breast cancer

Kang,

Kim,

Lee

et al. 2024

Preprint

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Immunohistochemical (IHC) staining pattern of p53 has been recognized as a potential surrogate marker for TP53 mutations across diverse cancer types. Nevertheless, interpretative criteria for p53 IHC expression as a predictive tool for TP53 mutation in triple-negative breast cancer (TNBC) have not been established yet. A total of 113 TNBC cases were analyzed for p53 IHC pattern and somatic TP53 mutation using whole exome sequencing. Functional properties of TP53 mutations were determined using the National Cancer Institute (NCI) TP53 database. P53 IHC staining patterns fell into three distinct categories: nuclear overexpression (n = 58), absence of staining indicating null pattern (n = 40), and wild-type expression (n = 15). The cutoff for predictive p53 nuclear overexpression was determined to be 80%. This threshold correlated strongly with TP53 mutations. Notably, nuclear overexpression had a positive predictive value (PPV) of 83% for missense or in-frame mutations, while the null pattern showed a PPV of 85% for detecting nonsense, frameshift, or splicing mutations. Furthermore, p53 overexpression was significantly linked to missense mutations within the DNA-binding domain (DBD) exhibiting gain-of-functon(GOF) or dominant-negative effect (DNE). Cases exhibiting both nuclear overexpression and cytoplasmic expression (n = 5) were correlated with nonsense or frameshift mutations affecting the DBD, NLS, or splice sites. Subclonal p53 staining patterns observed in 7 cases were found to be associated with TP53 mutations. Our study proposes newly defined criteria for interpreting p53 immunostaining patterns in TNBC, potentially allowing for the prediction of TP53 mutation types and their functional implications.

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