Transcriptional Regulation by Wild-Type and Cancer-Related Mutant Forms of p53

Abstract

TP53 missense mutations produce a mutant p53 protein that cannot activate the p53 tumor suppressive transcriptional response, which is the primary selective pressure for TP53 mutation. Specific codons of TP53, termed hotspot mutants, are mutated at elevated frequency. Hotspot forms of mutant p53 possess oncogenic properties in addition to being deficient in tumor suppression. Such p53 mutants accumulate to high levels in the cells they inhabit, causing transcriptional alterations that produce pro-oncogenic activities, such as increased pro-growth signaling, invasiveness, and metastases. These forms of mutant p53 very likely use features of wild-type p53, such as interactions with the transcriptional machinery, to produce oncogenic effects. In this review, we discuss commonalities between wild-type and mutant p53 proteins with an emphasis on transcriptional processes.

Mutant p53-Associated Molecular Mechanisms of ROS Regulation in Cancer Cells

“…Indeed, mutations of TP53 are harbored in all coding exons, but predominantly cluster in exons 4-9 corresponding to the DBD. Within this region, the most frequent mutations, known as hotspots, are divided into two categories: conformational mutations that lead to structural changes in the binding domain, and contact mutations, that alter the ability of the protein to bind DNA [76]. In both cases, these mutations alter the interaction of p53 with its consensus DNA-binding sequence, impairing the activation of p53 target genes involved in suppressing tumor growth.…”

PVT1 Long Non-coding RNA in Gastrointestinal Cancer

“…In colorectal cancer, PVT1 transcription is influenced by p53 (50). This tumor suppressor is involved in the cell cycle regulation by transactivating a plethora of protein-coding but also nonprotein-coding genes, that ultimately prevent cell division by inducing cell cycle arrest, senescence, or apoptosis (88,89). Importantly, p53 is the most frequently mutated gene in human cancers (90,91).…”

Do Mutations Turn p53 into an Oncogene?

“…Indeed, the gene is not frequently deleted but is mainly subject to mutations, the majority of which are missense mutations located in the DNA binding domain [50] (Figure 1). Within this region, the most frequent mutations, known as hot spots, are divided into two categories: conformational mutations (e.g., R175H) that lead to structural changes in the binding domain, and contact mutations (e.g., R273H), that alter the ability of the protein to bind DNA [51]. In both cases, these mutations alter the interaction of p53 with its consensus DNA-binding sequence, impairing the activation of p53 target genes involved in suppressing tumor growth.…”