Abstract
The key role of p53 as a tumor suppressor became clear when it was realized that this gene is mutated in 50% of human sporadic cancers, and germline mutations expose carriers to cancer risk throughout their lifespan. Mutations in this gene not only abolish the tumor suppressive functions of p53, but also equip the protein with new pro-oncogenic functions. Here, we review the mechanisms by which these new functions gained by p53 mutants promote tumorigenesis.
Highlights
TP53 (Tumor Protein P53) is among the most extensively studied human genes [1,2]
The transcription factor p53 is the principal mediator of cellular responses to several stressors, such as DNA damage, oncogene activation, nutrient deprivation, and hypoxia [3,4]
P53 activity is negatively regulated by MDM2 (Mouse Double Minute 2), which binds to p53 and promotes its proteasomal degradation [5,6,7,8]
Summary
TP53 (Tumor Protein P53) is among the most extensively studied human genes [1,2]. The main explanation for this interest is its key role in preventing tumor development. GOF in p53 is supported by evidence that mice expressing p53 R172H or R270H mutants (equivalent to human R175H and R273H) develop a greater number of metastatic tumors than p53−/− mice [60,61], and by the observation that patients with Li-Fraumeni syndrome carrying p53 missense. The acquisition of p53 mutations during the advanced stage of the disease might confer cancer cells high genomic instability, a metastatic phenotype, and progression toward very aggressive PDACs. To date, mutant p53 has been shown to promote oncogenic cellular changes by interacting with other transcription factors (enhancing or impairing their transcriptional activity) or with chromatin-modifying complexes, leading to alterations in the cellular transcriptional profile. P53 mutants have been shown to affect multiple aspects of cellular behavior and phenotypes, such as metabolism, invasion, migration, and proliferation
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