Abstract
The tumor suppressor p53 (TP53) is the most frequently mutated human gene. Mutations in TP53 not only disrupt its tumor suppressor function, but also endow oncogenic gain-of-function (GOF) activities in a manner independent of wild-type TP53 (wtp53). Mutant TP53 (mutp53) GOF is mainly mediated by its binding with other tumor suppressive or oncogenic proteins. Increasing evidence indicates that stabilization of mutp53 is crucial for its GOF activity. However, little is known about factors that alter mutp53 stability and its oncogenic GOF activities. In this review article, we primarily summarize key regulators of mutp53 stability/activities, including genotoxic stress, post-translational modifications, ubiquitin ligases, and molecular chaperones, as well as a single nucleotide polymorphism (SNP) and dimer-forming mutations in mutp53.
Highlights
The primary role of the tumor suppressor p53 (TP53) is to control cell cycle progression, senescence, DNA repair, cell death, and cell metabolism, leading to inhibition of tumorigenesis [1,2]
Many review articles describe mutp53-binding partners and their as gain of function (GOF) mechanisms [8,15,16,17,18,19,20,21], a few reviews address upstream factors and postpost-translational modifications (PTMs) that alter mutp53 downstream signaling as GOF mechanisms [8,15,16,17,18,19,20,21], a few reviews address upstream factors and stability and its oncogenic GOF activities which are the main focus of this review paper
These results suggest that mutp53 stability is regulated by the level of glucose, and deacetylation at the C-terminal lysine residues is involved in the glucose restriction-mediated mutp53 degradation
Summary
The primary role of the tumor suppressor p53 (TP53) is to control cell cycle progression, senescence, DNA repair, cell death, and cell metabolism, leading to inhibition of tumorigenesis [1,2]. The presence of mutant TP53 (mutp53) is associated with advanced stages of disease, metastasis, recurrence, and patient’s poor prognosis, even when compared with TP53 deletion [4,5,6] Such oncogenic activities of mutp are referred to as gain of function (GOF) [7]. Conformational mutants robustly alter the TP53 structure and disrupt disrupt the DNA binding activity [26,27]. Many review articles describe mutp53-binding partners and their as GOF mechanisms [8,15,16,17,18,19,20,21], a few reviews address upstream factors and PTMs that alter mutp downstream signaling as GOF mechanisms [8,15,16,17,18,19,20,21], a few reviews address upstream factors and stability and its oncogenic GOF activities which are the main focus of this review paper. PTMs that alter mutp stability and its oncogenic GOF activities which are the main focus of this review paper
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