TP53 in Biology and Treatment of Osteosarcoma

Abstract

The TP53 gene is mutated in 50% of human tumors. Oncogenic functions of mutant TP53 maintain tumor cell proliferation and tumor growth also in osteosarcomas. We collected data on TP53 mutations in patients to indicate which are more common and describe their role in in vitro and animal models. We also describe animal models with TP53 dysfunction, which provide a good platform for testing the potential therapeutic approaches. Finally, we have indicated a whole range of pharmacological compounds that modulate the action of p53, stabilize its mutated versions or lead to its degradation, cause silencing or, on the contrary, induce the expression of its functional version in genetic therapy. Although many of the described therapies are at the preclinical testing stage, they offer hope for a change in the approach to osteosarcoma treatment based on TP53 targeting in the future.

Keywords: TP53; animal models; gene therapy; osteosarcoma; pharmacological modulation.

Figure 1

The main functions of p53 in the cell life and death.

Figure 2

The primary structure of p53 protein with marked domains and amino acid codons showing the number of missense mutations. The X-axis represents the p53 amino acid sequence, Y-axis number of found substitutions. Transactivation domain (green); Core domain which can bind DNA (red); oligomerization domain (blue). Figure created basing on the data published in references [80,81,82,83,84,85,86,87,88,89,90,91,92,93] using cBioPortal Mutation Mapper [94,95].

Figure 3

The main targets for pharmacological p53 modulation and selected molecules targeting p53-dependent pathways.