Repair or perish – the role of p53 protein in a cell’s life

Abstract

The p53 protein is one of the most important suppressors of neoplastic transformation. It regulates transcription of multiple genes and interacts directly with other proteins. It plays a significant role in the most important processes that take place in the cell, including: DNA repair, cell cycle and programmed cell death-apoptosis. Loss of its proper function leads to a disturbance of the mechanisms controlling cell proliferation and survival, which contributes to the development of neoplasms. The TP53 gene is called the guardian of the genome. Its mutations occur in a large percentage of tumors. They most often concern sequences that encode the DNA-binding domain (exons 5-8). The TP53 gene, together with the TP63 and TP73 genes, belongs to the oldest evolutionary family of cancer transformation suppressors. Its product, a full length p53 protein, consists of five domains and a flexible consolidator region and functions as a homotetramer. The regulation of p53 activity is caused by MDM2 protein, which contributes to proteasomal degradation of the suppressor. This review deals with the most important aspects of the regulation of cell activity by p53 protein. It describes the structure of p53 protein and the associated therapeutic possibilities.

PROM1, CXCL8, RUNX1, NAV1 and TP73 genes as independent markers predictive of prognosis or response to treatment in two cohorts of high-grade serous ovarian cancer patients

“…It is also associated with the control of cell metabolism, autophagy and cell senescence [18]. On the other hand, when altered, p53 can acquire new capabilities (gain-of-function mutations) [19], and when it becomes nonfunctional, an environment promoting the activity of oncogenes is created, as shown in our previous research [6,7].The occurrence of TP53 mutations, especially of the missense type, considerably speeds up tumorigenesis [20]. In line with these findings, three oncogenes analyzed in the experimental cohort, i.e., CD44, MKI67 and RUNX2, exerted opposed effects on patient DFS depending on the TP53 mutation status.…”

“…Interestingly, the three genes revealed their adverse prognostic value in tumors harboring the TP53 missense mutations, thus supporting the aforementioned superior role of p53 in carcinogenesis. By contrast, the positive impact of CD44, MKI67 and RUNX2 overexpression on HGSOC patient survival is likely caused by their proliferation-promoting function which, in turn, sensitizes cancer cells with the normal p53 protein to cisplatin and other DNA-damaging agents [20]. In fact, the p53-mediated inhibition of CD44 was shown to enable untransformed cells to respond to stress-induced, p53-dependent cytostatic and apoptotic signals.…”

“…Considering over 70% similarity of the DNA-binding domains in p53, p63 and p73 proteins, many known p53 target genes (e.g., CDKN1A (p21), PUMA, NOXA, BAX and MDM2) have been demonstrated to be regulated by the other members of this protein family, too. Nevertheless, the full repertoire of common and private target genes for each suppressor still needs to be unraveled [20]. Interestingly, the oligomerization domains in these proteins are much less conserved.…”

“…This region, missing in the p53 protein, is considered to interact with the transactivation domain of the second protein partner of a dimer, thus inhibiting the transactivation properties of the entire complex [25]. Unlike the TP53, the TP63 and TP73 genes are rarely mutated in neoplastic cells [20]. Accordingly, in the validation cohort, we found one potentially harmful sequence variant in TP73 (SNP with a moderate impact), no alterations in TP63 (data not shown) and as much as 59 mutations in the TP53 gene (Table 3 and S4).…”

Clinical significance of TP53 alterations in advanced NSCLC patients treated with EGFR, ALK and ROS1 tyrosine kinase inhibitors: An update

“…The TP53 gene is located on the short arm of the chromosome 17 (17p13.1) and consists of 11 exons that code for the 393 amino acid p53 protein localized in the nucleus and cytoplasm. The p53 comprises functional domains: the N-terminal transactivation domain (TAD, residues 1-67), the proline-rich domain (PRD, residues 68-98), the DNA-binding domain (DBD, residues 99-303), the tetramerization domain (TET, residues 323-363), and the C-terminal regulatory domain (CTD, residues 364-393) [17][18][19]. Briefly, the TAD is subdivided into two regions: TAD1 and TAD2, which allow p53 to bind to different cofactors, and are required for p53-mediated suppression of tumorigenesis in response to stress.…”