Tumor suppressor gene Introduction

Tumor suppressor gene, also known as anti-cancer gene. Some types of cancer cells with normal fibroblast cell fusion, hybrid cells obtained as long as the future generations to retain some pro-normal performance of the chromosome can be normal when the phenotype, but also with the loss of chromosome re-emergence of malignant cells. This phenomenon showed that some chromosomes may inhibit tumor gene, and their loss, or loss of function mutation, so that activation play a role in cancer and cancer-causing gene.
To generate a variety of cancer genes and genes other than changes in a single cancer-causing mutation is not sufficient, the accumulation of multiple genetic changes can be cited directly control cell growth and differentiation mechanism of disorder, so that out-of-control cell proliferation and carcinogenesis. Changes in these genes in the two most common genetic abnormalities is: cancer genes (oncogenes) and tumor suppressor genes (cancer suppressor genes, also known as tumor suppressor genes, tumor supp ressor genes, or anti-cancer genes, anti - oncogenes) changes.
Oncogene is the product of the encoding and transformation of cells of the tumor-related genes. It is the role of dominant manner, positive effect on cell growth and to promote cell transformation. Many cancer gene mutation as a result of single base, leading to cancer gene product in a single amino acid substitution, and the loss of its regulation of the activity. The first identified human ras oncogene is a gene. ras gene family is closely related to members of the three: H-ras, K-ras and N-ras in human tumors is the most common cancer genes, they are about 15% of human dioxin were detected in the tumor, including 50 % of colon cancer and 25% of lung cancer.
When the normal tumor suppressor genes inhibit cell proliferation and the role of tumor. Many tumors are found in the two tumor suppressor genes or inactivation of allelic loss, loss of negative regulation of cell proliferation factors, and thus the transformation of the tumor cells and the role of dysplasia. Located in the Rb gene on chromosome 13p14 is the first identification was found and the tumor suppressor gene, which is rare in children, retinoblastoma found.

Knud-son he is through epidemiological survey found that this type of tumor in 40 percent of a family, a genetic tendency to occur in infants of multiple bilateral tumors occurred常呈, such as early and bolt for the surgical resection, still occur in patients when they grow up, such as the risk of osteosarcoma. The remaining 60% for sporadic and no family history, occurred in young children, often force the side of a single tumor, post less. Knudson According to statistical analysis, the "two-hit" hypothesis to explain these two types of tumors. In familial cases, the first "blow" (mutations) occurring in germ-line cells, from the genetic parents of a defective copy of the defective Rb itself is not sufficient to stimulate the occurrence of tumor. Occurred in the somatic cell's second "blow" (mutation), resulting in the loss of the remaining normal copy of the Rb allele. In sporadic cases, two "blow" to both of which occurred in with the whole cells (retinoblastoma), so that the two normal alleles are mutations in Rb and inactivation. Such opportunities are usually less (1 / 30000). Cytogenetic study found that in some patients with retinoblastoma cells in the deletion of chromosome 13p14, suggesting that loss of Rb gene may lead to the occurrence of tumor. Southern blot technique using measured bolt restriction fragment length polymorphism (RFLP) can detect the normal allele loss of heterozygosity (loss kf heterozygosity, LOH). Experiment also proved that gene transfer is in charge of the introduction of the Rb gene into cultured retinoblastoma or osteosarcoma cells can reverse their tumorigenicity. These fully proved Rb gene is a tumor suppressor gene. Although the Rb gene is rare in children in retinoblastoma was found and identified, but also some common adult tumors, such as bladder cancer, breast cancer and lung cancer found in its loss or inactivation.


Was also some common adult tumors, such as bladder cancer, breast cancer and lung cancer found in its loss or inactivation. Some tumor suppressor gene mutations in human tumors is the most common molecular change. The second was identified as a tumor suppressor gene p53 in the majority of human cancers such as leukemia, lymphoma, sarcoma, brain tumor, breast cancer, gastrointestinal cancer and lung cancer in the inactivation phenomenon常呈. p53 mutations can be found in up to 50% of cancer, it is the evil of human tumor the most common genetic change.

Hereditary Li-Fraumeni cancer syndrome, the head of the family members see the Department of cells have a p53 mutation. Can occur in patients with osteosarcoma was young, his family members can occur adrenocortical carcinoma, breast cancer and brain tumors and many other types of malignant tumors. p53 mutations can occur adrenocortical carcinoma, breast cancer and brain tumors and many other types of malignant tumors. product of p53 gene regulation of cell cycle and apoptosis. Factor-induced mutagenic DNA damage induced rapid p53, its activation of cyclin-dependent kinase (cdk) inhibitor p21 transcription. p53 production line can block the cell cycle at G1 phase, combined with proliferating cell nuclear antigen (PCNA) and inhibit DNA replication, so that the DNA damage before replication repair in time. If not, it may lead to apoptosis, removal of the cells carrying the mutation. P53 mutations and the product will lose the cell cycle after DNA damage the ability to come to a halt, resulting in an increase in mutation frequency and cell genome instability. This genomic instability is a common feature of cancer cells, it can be in the tumor progression of oncogenes and tumor suppressor genes play a role to further the accumulation of changes. The lack of p53 apoptosis of tumor cells can not maintain the survival of tumor cells, but also increased the chemotherapy and radiotherapy resistance and resistance. p53 inactivation of tumor cells to survive these roles, explained the high frequency of human malignant tumors of the p53 mutation.
A new tumor suppressor gene are constantly emerging, such as breast cancer is closely related to BRCA1 and BRCA2, and pancreatic cancer-related DPC4, and renal cell carcinoma and other VHL-related tumor suppressor gene have been found; also related with liver cancer M6P/IGF2r gene, located on chromosome 3p14.2, such as the FHIT gene is a candidate tumor suppressor gene.
Is a product of tumor suppressor genes inhibit cell proliferation, promote cell differentiation, and inhibition of cell migration, so play the role of negative regulation, is generally believed that mutations in tumor suppressor gene is recessive.
The product of tumor suppressor genes include (Table 16-2): ① transcription regulatory factors, such as Rb, p53; ② negative regulation of transcription factors, such as WT; ③ cyclin-dependent kinase inhibitor (CKI), such as p15, p16, p21; ④ inhibitory factor signaling pathway, such as the ras GTP-activating protein (NF-1), phospholipase (PTEN); ⑥ DNA repair factors, such as BRCA1, BRCA2. ⑥ with the development and proliferation of stem cell signaling pathway related components, such as: APC, Axin and so on.
Inactivation of tumor suppressor gene ways: ① allele recessive role in the inactivation of tumor suppressor gene allele hidden in the cells from the role of inactivation of one copy and another copy is still the existence of wild-type cells phenotype was normal. Only when another copy after inactivation lead to tumorigenesis, such as the Rb gene. ② tumor suppressor gene role in the dominant negative (dominant negative): copies of tumor suppressor gene mutation in another wild-type copy and the expression of the existence of circumstances, can make cells cancerous and malignant phenotype and function of wild-type copy inactivation. This role as the dominant negative effect or anti-dominant role. As confirmed in recent years, and APC mutant p53 protein, respectively, with wild-type protein binding to the inactivation, and transformed cells. ③ hypothesis less than haploid (Haplo-insufficiency): certain anti-cancer gene expression level is very important, if a copy of inactivation, and the other copy may not be sufficient to maintain normal cell function, resulting in tumorigenesis. Such as loss of DCC gene can make a copy is attached mucosa cells significantly reduced the loss of cell contact inhibition and thus to enable the expansion of cell clones or were malignant phenotype. Related to the inhibition of oncogene oncogene seems to be the role of these two types of genes in the contradictions of the fine balance between control of cell growth, they are generated in the interaction of cancer to fully illustrate the two opposites in nature between the yin and yang, allelopathy, complementary dialectical unity of the law. From the study of oncogenes and tumor suppressor gene interactions in a considerable number have been translated into the molecular basis for understanding. Cell growth is to promote cell cycle and suppression of the gene product of the gene product on its delicate balance between the results. Any kind arising from abnormal expression of oncogenes, such as a gene over-expression, or an inhibition of the inactivation of oncogenes may lead to uncontrolled cell growth. The generation of cancer is a cancer involving a variety of gene activation and inactivation of tumor suppressor genes accumulate changes in the multi-step process. When the regulation of oncogene and tumor suppressor gene increase the knowledge, the use of drugs or gene therapy intervention may be pregnant will also increase. Application of viral gene vector to replace the function of tumor suppressor genes, or surgical resection can not be the expression of cancer patients with antisense oncogene components in order to enable or inhibit tumor regression, and the combination of systemic and prolong patient's life. More research on genes and tumor suppressor gene similar to the role of the rational development of new cancer treatment strategies is essential.