1. Discovery of the p53 gene
The p53 gene is found to be associated with tumors. In 1979, Lane and Crawford isolated a protein that interacted with SV40 large T antigen in mice infected with SV40. Because of its molecular weight of 53 kDa, it was named p53 (human gene called TP53). At first, p53 was mistaken for oncogenes. It was not until the 1990s that people recognized that p53, which causes tumor formation or cell carcinogenesis, is a mutation in the p53 gene. The wild-type p53 gene is an important tumor suppressor gene, which is a negative regulator in the cell growth cycle and plays an important role in many processes such as cell cycle regulation, DNA damage repair, cell differentiation, apoptosis and senescence, thus known as “cell guardian.” With the deepening of research, the p53 genes of various animal models such as monkey, chicken, rat, Xenopus laevis and zebrafish have also been cloned.

Among them, the human TP53 gene is located on chromosome 17P13.1, the mouse p53 gene is located on chromosome 11, and a non-functional pseudogene is found on chromosome 14. In these animals with different degrees of evolution, their p53 gene structure is exceptionally conserved. The gene is 16–20 kb in length and consists of 11 exons and 10 introns. The first exon does not encode a domain, and exons 2, 4, 5, 7, and 8 encode five evolutionarily highly conserved domains, respectively, which are transcribed to form an mRNA of about 2.5 kb. Later, on the basis of gene homology, other members of the p53 family, p73 and p63, which are named for their respective molecular weights, have similar structures and functions to p53.

2. P53 signaling pathway
The p53 gene is regulated by a variety of signaling factors. For example, when DNA damage or abnormal cell proliferation occurs in cells, the p53 gene is activated, causing cell cycle arrest and initiation of DNA repair mechanisms to repair damaged DNA. However, when DNA is badly damaged and cannot be repaired, p53, a transcription factor, can further activate transcription of a downstream pro-apoptotic gene, induce apoptosis, and kill cells with DNA damage. Otherwise, these DNA-damaged cells may gradually deviate from normal regulation and may eventually form tumors.

Although the mRNA level of p53 is high under normal conditions and there is a large amount of protein synthesis, p53 protein is easily degraded, so the level of p53 protein in normal cells is very low. The ubiquitination modification of proteins is the most common degradation mode in intracellular protein metabolism, and the degradation of p53 protein is also achieved by ubiquitination. MDM2 is a ubiquitinated E3 ligase specific for p53, which directly binds to p53 protein to promote ubiquitination of p53 protein and plays a key role in the dynamic balance of p53 protein in cells. MDM2 itself is also activated by p53 protein, so MDM2 is an important negative feedback regulator in the p53 pathway.

3. P53 and tumor
Although mice can produce offspring after their p53 gene was knocked out, high frequency spontaneous tumors appear during their growth and development, which suggests a close relationship between p53 protein and tumor. In fact, the TP53 gene is currently the most relevant gene in human tumors, and is associated with more than 50% of human malignancies. Abnormal expression and functional inactivation of the TP53 gene have been found in more than 51 human tumor cases. Mutation of TP53 gene is the main reason for its functional inactivation. More than 400 types of TP53 gene mutations have been discovered so far, of which 147 are related to gastrointestinal tumors. By analyzing the TP53 mutation site in a large number of tumor cases, it was confirmed that 95.1% of the p53 point mutation sites in the tumor occurred in highly conserved DNA binding regions, and the rate is the highest especially at positions 175, 245, 248, 249, 273 and 282.

In addition, some point mutations altered the spatial conformation of p53 and affected the interaction of p53 protein with proteins such as MDM2 and p300. Other point mutations occur in the nuclear localization signal region of p53, making it impossible for p53 to enter the nucleus to function as a transcriptional activation. The TP53 gene mutation sites of different tumors are not consistent. For example, G:C→A:T conversion accounts for 79% in colon cancer; in breast cancer, G→T transversion accounts for 1/4, and this mutation in Colon cancer is very rare; the TP53 gene mutation pattern of lymphoma and leukemia is similar to colon cancer; G:C→T:A mutation is the most common in lung cancer, and the frequency of G→T transversion in esophageal cancer is very high.

At present, p53 is the most important factor in the complex network and regulation system of tumor formation. Some people think that p53 is a good tumor diagnostic marker and can be used as an important indicator for early diagnosis of cancer. Recognizing the important role of the p53 gene, thousands of molecular biologists around the world are turning to their original research and turning to p53, hoping to use this as a breakthrough to overcome cancer. Scientists believe that the prospect of using p53 to discover and treat cancer is very broad. In addition to gene therapy, researchers are screening small molecule compounds such as small molecule inhibitors that can affect the regulation of the upstream and downstream of the p53 gene. A small molecule compound called nutlins developed by Roche Pharmaceuticals Inc., which interferes with the regulatory relationship between p53 and MDM2, is expected to be an effective anticancer drug.

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