Image: Thomas Splettstoesser
p53 is a tumor suppressor protein that is the most commonly mutated gene in tumor/cancer cells. p53 is the most important and most widely studied of the tumor suppressor genes. Mutations in p53 are found in approximately 50% of all human cancers. The most studied tumor suppressor function of p53 is tied to apoptosis (programmed cell death). Cancer therapies that involve mutated tumor suppressor genes like p53–including gene therapy, small molecule inhibitors, immunotherapy, epigenetic modulators, synthetic lethality, and combination therapies—have been an active area of research in cancer treatment. (Deppert, W. (2023, May). Tumor suppressor gene. AccessScience. https://www.accessscience.com/content/article/a800950)
Featured articles:
*Abuetabh, Y., Wu, H. H., Chai, C., Al Yousef, H., Persad, S., Sergi, C. M., & Leng, R. (2022). DNA damage response revisited: the p53 family and its regulators provide endless cancer therapy opportunities. Experimental & Molecular Medicine, 54(10), 1658-1669. [PDF] [Cited by]
“Antitumor therapeutic strategies that fundamentally rely on the induction of DNA damage to eradicate and inhibit the growth of cancer cells are integral approaches to cancer therapy. Although DNA-damaging therapies advance the battle with cancer, resistance, and recurrence following treatment are common. Thus, searching for vulnerabilities that facilitate the action of DNA-damaging agents by sensitizing cancer cells is an active research area. Therefore, it is crucial to decipher the detailed molecular events involved in DNA damage responses (DDRs) to DNA-damaging agents in cancer. The tumor suppressor p53 is active at the hub of the DDR. Researchers have identified an increasing number of genes regulated by p53 transcriptional functions that have been shown to be critical direct or indirect mediators of cell fate, cell cycle regulation, and DNA repair. Posttranslational modifications (PTMs) primarily orchestrate and direct the activity of p53 in response to DNA damage. Many molecules mediating PTMs on p53 have been identified. The anticancer potential realized by targeting these molecules has been shown through experiments and clinical trials to sensitize cancer cells to DNA-damaging agents. This review briefly acknowledges the complexity of DDR pathways/networks. We specifically focus on p53 regulators, protein kinases, and E3/E4 ubiquitin ligases and their anticancer potential.”
*Capuozzo, M., Santorsola, M., Bocchetti, M., Perri, F., Cascella, M., Granata, V., Celotto, V., Gualillo, O., Cossu, A. M., Nasti, G., Caraglia, M., & Ottaiano, A. (2022). p53: From Fundamental Biology to Clinical Applications in Cancer. Biology, 11(9), 1325. [PDF] [Cited by]
“p53 tumour suppressor gene is our major barrier against neoplastic transformation. It is involved in many cellular functions, including cell cycle arrest, senescence, DNA repair, apoptosis, autophagy, cell metabolism, ferroptosis, immune system regulation, generation of reactive oxygen species, mitochondrial function, global regulation of gene expression, miRNAs, etc. Its crucial importance is denounced by the high percentage of amino acid sequence identity between very different species (Homo sapiens, Drosophila melanogaster, Rattus norvegicus, Danio rerio, Canis lupus familiaris, Gekko japonicus). Many of its activities allowed life on Earth (e.g., repair from radiation-induced DNA damage) and directly contribute to its tumour suppressor function. In this review, we provide paramount information on p53, from its discovery, which is an interesting paradigm of science evolution, to potential clinical applications in anti-cancer treatment. The description of the fundamental biology of p53 is enriched by specific information on the structure and function of the protein as well by tumour/host evolutionistic perspectives of its role.”
*Hibino, E., & Hiroaki, H. (2022). Potential of rescue and reactivation of tumor suppressor p53 for cancer therapy. Biophysical Reviews, 14(1), 267-275. [Cited by]
“The tumor suppressor protein p53, a transcription product of the anti-oncogene TP53, is a critical factor in preventing cellular cancerization and killing cancer cells by inducing apoptosis. As a result, p53 is often referred to as the “guardian of the genome.” Almost half of cancers possess genetic mutations in the TP53 gene, and most of these mutations result in the malfunction of p53, which promotes aggregation. In some cases, the product of the TP53 mutant allele shows higher aggregation propensity; the mutant co-aggregates with the normal (functional) p53 protein, thus losing cellular activity of the p53 guardian. Cancer might also progress because of the proteolytic degradation of p53 by activated E3 ubiquitination enzymes, MDM2 and MDM4. The inhibition of the specific interaction between MDM2 (MDM4) and p53 also results in increased p53 activity in cancer cells. Although the molecular targets of the drugs are different, two drug discovery strategies with a common goal, “rescuing p53 protein,” have recently emerged. To conduct this approach, various biophysical methods of protein characterization were employed. In this review, we focus on these two independent strategies based on the unique biophysical features of the p53 protein.”
*Wang, H., Guo, M., Wei, H., & Chen, Y. (2023). Targeting p53 pathways: mechanisms, structures, and advances in therapy. Signal Transduction and Targeted Therapy, 8(1), 92. [PDF] [Cited by]
“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.”
*Zhao, L., & Sanyal, S. (2022). p53 Isoforms as Cancer Biomarkers and Therapeutic Targets. Cancers, 14(13), 3145. [PDF] [Cited by]
“This review aims to summarize the implications of the major isoforms of the tumor suppressor protein p53 in aggressive cancer development. The current knowledge of p53 isoforms, their involvement in cell-signaling pathways, and their interactions with other cellular proteins or factors suggests the existence of an intricate molecular network that regulates their oncogenic function. Moreover, existing literature about the involvement of the p53 isoforms in various cancers leads to the proposition of therapeutic solutions by altering the cellular levels of the p53 isoforms. This review thus summarizes how the major p53 isoforms Δ40p53α/β/γ, Δ133p53α/β/γ, and Δ160p53α/β/γ might have clinical relevance in the diagnosis and effective treatments of cancer.”
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