The Role of p53 Signaling in Colorectal Cancer

Abstract

The transcription factor p53 functions as a critical tumor suppressor by orchestrating a plethora of cellular responses such as DNA repair, cell cycle arrest, cellular senescence, cell death, cell differentiation, and metabolism. In unstressed cells, p53 levels are kept low due to its polyubiquitination by the E3 ubiquitin ligase MDM2. In response to various stress signals, including DNA damage and aberrant growth signals, the interaction between p53 and MDM2 is blocked and p53 becomes stabilized, allowing p53 to regulate a diverse set of cellular responses mainly through the transactivation of its target genes. The outcome of p53 activation is controlled by its dynamics, its interactions with other proteins, and post-translational modifications. Due to its involvement in several tumor-suppressing pathways, p53 function is frequently impaired in human cancers. In colorectal cancer (CRC), the TP53 gene is mutated in 43% of tumors, and the remaining tumors often have compromised p53 functioning because of alterations in the genes encoding proteins involved in p53 regulation, such as ATM (13%) or DNA-PKcs (11%). TP53 mutations in CRC are usually missense mutations that impair wild-type p53 function (loss-of-function) and that even might provide neo-morphic (gain-of-function) activities such as promoting cancer cell stemness, cell proliferation, invasion, and metastasis, thereby promoting cancer progression. Although the first compounds targeting p53 are in clinical trials, a better understanding of wild-type and mutant p53 functions will likely pave the way for novel CRC therapies.

NAMPT Inhibitor and P73 Activator Represses P53 R175H Mutated HNSCC Cell Proliferation in a Synergistic Manner

“…Previously, studies mostly focused on the loss of function (LoF) of the tumor suppressor role of wild-type p53, due to mutation, but, recently, there has been more focus on the gain of function (GoF) in mutant p53 proteins [5]. The acquisition of p53 GoF after a mutation is currently considered to occur via three mechanisms [6,7]. In the first, the mutant p53 directly binds to the novel binding site with a non-canonical sequence to activate a specific downstream gene [8].…”

Changes in the Transcriptome Caused by Mutations in the Ribosomal Protein uS10 Associated with a Predisposition to Colorectal Cancer

“…Thus, the increased activity of the MDM2 gene observed with the uS10 mut1 and uS10 mut3 proteins is obviously required for their effective disposal from the cell. This, in turn, should lead to an imbalance in the Mdm2-p53 network, the role of which in the progression of many types of tumors, including CRC, is well known [ 60 , 61 , 62 ], and, consequently, to the activation of some genes of the p53 pathway and the induction of cellular senescence. Remarkably, the amount of DEGs in uS10 mut3 -producing cells is much greater than that in uS10 mut1 -producing ones, which could be due to the higher pI value for uS10 mut3 (8.61) compared to the respective one for uS10 mut1 (6.06) and, therefore, to the higher affinity of uS10 mut3 for RNA.…”

The p53 Pathway Related Genes Predict the Prognosis of Colon Cancer

“…At the same time, the p53 gene is the gene with the highest correlation with human tumors so far, and its correlation with colon cancer has been widely studied and reported. 2 , 3 , 16 However, in colon cancer, the relationship between p53 pathway-related genes and patient prognosis is still unclear. In our study, we identified 3 ( CDKN2A, BAK1, BTG1 ) genes that are significantly related to PFS, and we believe that CDKN2A gene is an independent prognostic factor for PFS.…”