Targeting p53 pathways: mechanisms, structures and advances in therapy

Abstract

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.

Unveiling the Mechanisms of EGCG–p53 Interactions through Molecular Dynamics Simulations

“…In addition, in most cases, these regions formed an α-helical, a finding that is congruent with previous studies . Moreover, these α-helices are necessary for binding proteins, such as MDM2 and MDMX on Trp23 or high mobility group box 1 proteins (HMGB1) on Trp53. − …”

“…Furthermore, it is noteworthy that throughout the 500 ns simulation, none of the regions of interest exhibited the formation of α-helices. This finding holds significance as α-helices are essential for binding proteins such as MDM2 and MDMX. − Therefore, the interaction of ECGC within R2–1, coupled with its structural conformation, strengthens its inhibitory effect and renders these sites inaccessible. This could potentially enhance inhibition of the p53–MDM2 interaction.…”

The kinesin light chain‐2, a target of mRNA stabilizing protein HuR, inhibits p53 protein phosphorylation to promote radioresistance in NSCLC

“…It participates in various activities of cells, such as cell cycle arrest, apoptosis, autophagy, DNA repair, etc. 40 Studies comparing wild-type and p53 deficient mice show that p53 is necessary for radiation-induced cell apoptosis, 41 and p53 mutation increases the radioresistance of cancer cells, and partial recovery of p53 function causes radiosensitization. 42 Also, a previous study has shown that activation of the p53 signal pathway can improve the radiosensitivity of lung cancer.…”

Antitumor Effect of Epigallocatechin Gallate and Vincristine in Mice with L5178Y Lymphoma

“…Its relevance in cancer is such that it interacts with more than 100 proteins. All these functions mean that this oncoprotein can be used not only as a biomarker, but also as a therapeutic target for cancer, as an adjuvant therapy and as a targeted therapy [47]. But within the events of the cyclin mechanism, various points have also attracted attention as therapeutic targets.…”