Introduction of P53
The P53 family is a significant finding in cancer research, and its family members include: P53, P63 and P73. They act as transcription factors involved in the response of cells to stress and the process of ontogeny. Because of the similarity of structure and function, they constitute a family. Structurally, in addition to the promoters present before exon 1 of the p53, it also has a promoter within the gene. Thus, the choice of different promoters and the different splicing at the C-terminus will result in many isoforms. Functionally, P53 has become a hot spot in cancer research as a tumor suppressor gene, which mainly mediates cell cycle arrest, apoptosis, autophagy, metabolism and aging.
P53 is a protein that integrates various cellular stress signals to induce cell cycle arrest or programmed death through DNA damage. Therefore, if P53 is inactivation by mutation, it will lose the function of inhibiting the tumor and cause the cells to become cancer cells. In addition, it has been reported that the mutated P53 protein can get the function which promotes the spread and migration of cancer cells. According to previous studies, researchers find that P53 is highly conserved among drosophila, zebrafish, mice and humans and has a similar structure. It has 4 domains, and be named a transcriptional activation domain (TAD), a DNA binding domain, an oligomeric domain, and a C-terminal domain. The function of transcriptional activation domain is transcriptional activation of the target gene for expression; the DNA binding domain allows p53 protein to specifically bind to the promoter of the p53 target gene; the oligomeric domain allows them to form homomultimers, thereby converting it from an inactive monomer to an active multimer.
Human P53 mRNA of 2.5Kbs in length and translate into a protein of 393 amino acids with a size of 43.7KD, but its mobility is slower on SDS-PAGE due to its proline-rich, the band was retained at 53 KD and it was named P53. Since the gene contains an internal promoter, when it is expressed, P53 produces two N-terminals, P53 and ΔNp53. In addition, the C-terminus of P53 can shift splicing to produce a variety of different P53 isoforms (α, β, γ, etc.). Therefore, P53 has various isoforms, such as: p53α, p53β, p53γ, ΔNp53α, ΔNp53β, ΔNp53γ and so on. ΔNp53 can competitively bind to the promoter of downstream gene by p53 mediation. Since ΔNp53 does not have a transcriptional activation domain and it occupies the promoter of the target gene, p53 cannot activate the expression of the downstream target gene. This means that ΔNp53 has a function of antagonism for P53. As a housekeeping gene, P53 is expressed in every cell, and it can determine cell fate by sensing the cell pressure.
The Function and Regulation of P53
As a transcription factor, P53 regulates the expression of target genes by sensing external stress. In cells, P53 mainly regulates apoptosis, senescence, cell cycle arrest and the like. When a cell is stressed and damaged, the level of P53 is upregulate. And then P53 will mediate cell cycle arrest or gene expression related to cell apoptosis. If the damage is minor, P53, with the help of other factors and its isoforms, tends to the function of the cell cycle arrest, stops the replication of cell, and save time for DNA damage repair. The mechanism can avoid the wrong DNA being copied to the daughter cells; when DNA damage is severe, P53 function is biased towards programmed cell death with the help of various factors. P53 can induce cells to die when the damage cannot be repaired and avoid cancerization. Since P53 has multiple isoforms, it shows complex functions in the body. For example, under cellular stress conditions, P53β can increase the transcriptional activity of the bax gene, rather than the p21 gene, and cause apoptosis. Additionally, P53β can regulate the replication and senescence of cells by up-regulating the expression of microRNA-34a together with full-length p53. P53γ is extremely unstable and is easily degraded by ubiquitination and exists in both nucleus and cytoplasm. Δ40p53 is a protein associated with early development that has not been found in adult tissues. It can differentiate pluripotent stem cells into somatic cells by controlling full-length p53 activity. There is also a p53 isoform, Δ133p53, which has become a hot spot in cancer research in recent years. The P53 protein can directly bind to the p53 internal promoter and induce the expression of Δ133p53α. The expressed Δ133p53α can antagonize with p53, and the cell fate under stress conditions is biased toward cell cycle arrest and inhibits apoptosis. Under the condition of double-strand break, Δ133p53 was induced to express and mediate the repair of double-strand break repair by mediating the double-strand break related repair genes rad51, rad52 and lig4.
As a transcription factor that determines cell fate, p53 needs to be tightly regulated. In normal human cells, P53 remains at a lower level due to HDM2-mediated ubiquitination degradation; when cells are exposed to external stress such as DNA double-strand breaks, oxidative stress, mitotic dysfunction, tissue hypoxia, oncogene activation and so on, the content of HDM2 in the cells decreased, and the inhibition was reduced. In addition, P53 is modified under external pressure, and the modified p53 not only relieves the inhibitory effect of HDM2 but also enhances its own stability and viability. And then the P53 regulates the expression of downstream related genes or activates related signals through interaction between proteins. In a word, stress response is exerted in cell. If the signal of external pressure is strong, the cells cannot survive by DNA damage repair or other ways, and the cells will die by p53-mediated programmed cell death to avoid transmitting the damage to the daughter cells.
P53 and Cancer
Depending on the function of P53, we can know that it is a typical tumor suppressor gene. When the P53 is mutation and inactivation, it will cause abnormal cell proliferation and canceration of the cells. In 50% of tumors, missense mutations occur in p53, and mutant p53 is associated with cancer and is an oncogene. According to previous studies, researchers find that mice with mutant p53 are more likely to develop cancer than null-p53 mice. Moreover, mutant p53 can escape ubiquitination and prolong the half-life to cause cancer. Therefore, p53 is closely related to tumorigenesis as a key regulator of cell fate in the cell. Its deletion and missense mutations at some sites can induce tumor production or further deterioration. It is also an important parameter that can be used for diagnosis and evaluation in cancer treatment.