What Is a Tumor Suppressor Gene?

p53 gene, human tumor suppressor gene. The gene encodes a protein with a molecular weight of 43.7KDa, but because the protein band appears at 53KDa shown by Marker, it is named P53. Because the protein contains a large amount of proline, the electrophoresis speed is slowed down. The inactivation of p53 gene plays an important role in tumor formation. The mdm2 ^[1] mutation ^[2] does not coexist with the P53 mutation. p53 is an important anti-cancer gene. Its wild-type makes cancer cells apoptotic, thereby preventing canceration. It also has the function of helping cell genes repair defects. Mutations of p53 increase canceration.

p53 gene

p53 gene, human

p53 is a

After the P53 gene was found in humans, monkeys, chickens and mice,

The N-terminus of P53 protein is amino acid residues at positions 1 to 80 in the acidic region, and the C-terminus is amino acid residues at positions 319-393 in the basic region. Normal P53 protein is easily hydrolyzed in cells, and its half-life is 20 minutes. Mutant P53 protein half-life It ranges from 1.4 to 7 hours. The N-terminus of P53 protein has an acidic domain similar to a transcription factor. When recombined with the DNA binding region of GAL4, the fusion protein can activate the transcription of GAL4 operon, and the activation function is located at 20th to 40th of P53. Codons, P53 cell localization and transactivation function suggest that the P53 protein may participate in transcriptional control directly or through interaction with other proteins.

The DNA binding and transactivation of P53 protein also suggested its involvement in cell growth regulation. Flow cytometry was used to determine the expression of P53 in the cell cycle of individual cells. It was found that activated lymphocytes had more P53 expression than non-activated cells. And it increased with the cells from G1 to S phase to G2, M phase, suggesting that the correlation between P53 expression and cell growth is higher than entering the cell cycle or a specific moment in the cycle. Transfection with a plasmid encoding antisense P53RNA non-transformation Cells cause the cell growth to stop completely, and P53 antibody injection will enter the stationary cells of the growth cycle. It can inhibit the cells from entering the S phase, suggesting that P53 may be necessary for Go / G1-S conversion, but P53 antibodies have no effect on cells from dividing to S phase Sodium dibutyrate, which has an inhibitory effect on G1 cells, also inhibits P53 synthesis. These results suggest that P53's regulatory effect on cell growth is at least from G0-G1, or G1-S, but its mechanism of action has not yet been clarified. P53 protein can regulate cell growth by regulating Cipt gene expression, that is, P53 protein can stimulate Cipt gene to produce a protein with a molecular weight of 21KD. This protein can effectively inhibit certain enzyme activities that promote cells to enter mitosis through the cell cycle, thereby inhibiting cell growth. In addition, the inhibitory effect of P53 was accompanied by a decrease in the expression of cell growth nuclear antigen strains. Cell growth and nuclear antigens are involved in cellular DNA replication. Therefore, P53 may play a role by inhibiting cellular genes or gene products related to DNA replication.

Block the cell cycle

In the cell cycle, the regulatory function of P53 is mainly reflected in the monitoring of G1 and G2 / M correction points, which is closely related to the activation of transcription. The P53 downstream gene P21 encodes a protein that is Cyclin-dependent

The interaction of P53 protein with other proteins and mutations of P53 gene can cause the loss of normal biological functions.

P53 and protein interaction

Some proteins can interact with the P53 protein, leading to the loss of its normal biological function.

P53 gene is related to 50% of human tumors, including liver cancer, breast cancer, bladder cancer, gastric cancer, colon cancer, prostate cancer, soft tissue sarcoma, ovarian cancer, brain tumor, lymphoma, esophageal cancer, lung cancer, osteosarcoma, etc. P53 mutations in human tumors are mainly in highly conserved regions, with the highest mutations at 175, 248, 249, 273, and 282. Different types of tumors, such as colon cancer and breast cancer, have similar epidemiology (including regional distribution and risk Factors), but the P53 mutation spectrum is not consistent. Colon cancer G: CA: T conversion accounts for 79%, and most CpG, dinucleotide sites, more than 50% of the conversion mutations occur in the 3rd to 5th domains of CpGC in the code 175, 248, 273); in breast cancer, only 13% of the transitions were found at the CpG site. In addition, GT transversions accounted for 1/4 in breast cancer, but T scores were rare in colon cancer. P53 in lymphoma and leukemia The mutation method is similar to that of colon cancer, that is, most mutations are converted to CPG sites, G T transversion is lower, and A: T G: C mutations are higher at A: T. Bai

Introduction

Gene therapy refers to biomedical treatment based on altering human genetic material. It is to introduce human normal genes or therapeutic DNA into human target cells in a certain way to correct gene defects or play a therapeutic role. So gene therapy targets the root cause of the diseasethe abnormal gene itself.

Cancer is a genetic disease. It is a multi-phase long-term evolution process of human cells under the influence of external environmental factors. Cancer is a killer that seriously threatens human health and life. China has more than 2.5 million new cancer patients each year, no less than 6 million patients being treated each year, and treatment costs exceeding 150 billion yuan. The main treatments for tumors are surgery, radiation therapy, and chemotherapy. Although medical scientists continue to improve these three major treatments, many cancer patients still have difficulty curing. People are paying more and more attention to improving the cure rate of tumors through the method of cure. Gene therapy is the only way for humans to overcome tumors in the 21st century.

effect

The p53 gene is the most thoroughly studied and most powerful tumor suppressor gene. Wild-type p53 plays a key role in cell cycle and apoptosis, especially for cancer cells that have been hit by irradiation, cytotoxic agents, and hyperthermia. Its main functions are:

Inhibit and kill tumor cells; synergize with radiotherapy and chemotherapy to enhance its efficacy in killing cancer cells to achieve

The effect of 1 + 1 is greater than 2;

Inhibit tumor angiogenesis and effectively prevent tumor recurrence and metastasis. Improve the body's own immune function;

The domestically produced recombinant human p53 adenovirus injection (brand name Jinshengsheng), after 5 years of arduous clinical trials, led by Zhang Shanwen of Beijing Cancer Hospital, medical staff in the radiotherapy department. Based on the completion of the phase clinical safety test, The phase II clinical trial of head and neck squamous cell carcinoma was successfully completed, which fully proved that it is safe and effective for the treatment of head and neck squamous cell carcinoma. On October 16, 2003, the State Food and Drug Administration approved the new certificate of recombinant human p53 adenovirus injection, which means that the world's first cancer gene therapy drug was born in China, marking China's gene therapy cancer clinical and gene drug industry In terms of transformation, they are at the forefront of the world.

prospect

Recombinant human p53 adenovirus is a genetically engineered live virus that is structurally composed of two parts: one is the tumor suppressor gene p53, and the other is the vector. The vector is a modified, replication-incompetent adenovirus. Just like rockets carry satellites into space, this p53-bearing adenovirus specifically infects tumor cells. It can effectively transfer the p53 gene for treatment into tumor cells without harming normal cells.

In this case, 53 cases of squamous cell carcinoma of the head and neck were treated with radiotherapy, and the complete disappearance rate of tumor was twice as high as that of 46 cases. Combined with radiotherapy for 45 cases of nasopharyngeal carcinoma, the complete tumor disappearance rate was 1.7 times higher than that of 41 cases with radiotherapy alone. Combined with radiotherapy, 4 cases of inoperable stage cervical cancers had completely disappeared. Combined with radiotherapy, chemotherapy or hyperthermia, various soft tissue sarcomas, digestive system adenocarcinomas, and ovarian cancers have all achieved certain effects. These cases are all patients who have failed treatment by 3 major methods. In the treatment of malignant tumors with Jinshengsheng, no toxic or side effects were found except for temporary self-limiting fever. In the future, comprehensive clinical trials will be carried out in order in other tertiary hospitals, and p53 gene therapy has moved from laboratory to clinical and industrialized.

p53 gene therapy tumors are just a good start, bringing new hope and dawn for humans to conquer cancer