Tumor suppressor

Many human genes produce proteins called tumor suppressors. Tumor suppressors inhibit transcription of genes that would cause increased replication. When a mutation occurs in any of these suppressors, replication and division become uncontrolled and tumors result. Table 14.3 lists some human tumor-suppressor genes. 

A 53-kDa protein designated p53 has become the focus of feverish activity in cancer research. Mutations in the gene that codes for p53 are found in more than half of all human cancers. When the gene is operating normally, it acts as a tumor suppressor when it is mutated, it is involved in a wide variety of cancers. By the end of 1993, mutations in the p53 gene had been found in 51 types of human tumors. The role of p53 is to slow down cell division and to promote cell death (apoptosis) under certain circumstances, including when DNA is damaged or when cells are infected by viruses. 

The important point is that two different mechanisms are operating here. One is analogous to the brakes failing in your car (inadequate or defective p53 protein) and the other (overproduction of CDKs) is equivalent to the accelerator 

Representative Tumor-Suppressor Genes Implicated in Human Tumors Tumor-Suppressor  

RBI Retinoblastoma osteosarcoma carcinoma of breast, bladder, and lung 

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Harris, C., Hollstein, M. Clinical implications of the p53 tumor-suppressor gene. N. Engl. f. Med. 

Jeffrey, P.D., Gorina, S., Pavletich, N.P. Crystal structure of the tetramerization domain of the p53 tumor suppressor at 1.7 Angstroms. Science 267 1498-1502, 1995. 

In apoptotic cell death, several factors such as growth factors, NO, the tumor suppressor gene p53, and the protein encoded by this gene contribute to the process that leads to cell death. One of the functions of p53 protein is the activation of apoptosis if a cell is transformed to a malignant cell. Apoptosis typically leads to the formation of smaller membrane-encapsulated particles within the cell. Apoptotic cell death begins in the nucleus and proceeds to other parts of the cell. The death process may be quite advanced before it can... 

Nucleic acids in the DNA contain a high number of nucleophilic sites that can be attacked by electrophilic intermediates (metabolites) of chemical compounds. DNA adducts formed may cause alterations in the expression of a critical gene in the cell and thus lead to cell death. For example, modification of p53 tumor suppressor gene may inactivate the functions of the p53 protein and render cells sensitive to malignant transformation. Also, formation of RNA adducts may inhibit key cellular events because RNA is essential for protein synthesis. 

TABLE 5.22 Important Oncogenes and Tumor Suppressor Genes in Human Cancers... 

In Drosophila, Fat functions as a tumor suppressor gene and dachsous is involved in thorax, leg, and wing development. Several human and mouse homologs have been identified. FAT1 regulates actin filaments, and the Fail knockout leads to defects in glomerular slit formation [3]. 

Post synaptic density protein/Drosophila disc large tumor suppressor/zonula occuldens-1 protein... 

Multiple cancers (co- Tumor suppressor effects To be determined... 

Abbreviations LDL, low density lipoprotein TNF-a, tumor necrosis factor-a IL-6, interleukin-6 APC, adenomatous polyposis coli tumor suppressor. 

PTEN is a phosphatase, which is a product of a tumor suppressor gene. This phosphatase has an unusual broad specificity and can remove phosphate groups attached to serine, threonine, and tyrosine residues. It is believed that its ability to dephosphorylate phosphati-dylinositol (PI) 3,4,5-triphosphate, the product of PI-3 kinase, is responsible for its tumor suppressor effects. 

TOR Signalling. Table 1 Protooncoproteins and tumor suppressors in the mTOR signalling network... 

Tumor suppressors Name and description of corresponding hamartoma syndrome... 

The recent links made between mTORCl and tumor suppressors/oncoproteins suggests that aberrantly high mTORCl activity may be the underlying cause of hamartomas and perhaps some cancers. Based on this, many clinical trials are underway to determine the efficacy of rapalogs as anti-cancer agents. Current phase III clinical trials include ... 

Transforming growth factor-beta (TGF- 3) proteins are multifunctional morphogens that control cell proliferation, differentiation and apoptosis, as well as cell migration and immune surveillance. TGF-(3 acts as a tumor suppressor, but can also act as a tumor promoter in... 

Despite the large number of molecules found to interact with the TGF- 3 pathway, few have been identified as functional tumor suppressors using either mouse or human genetics. The TGF-beta pathway is inactivated in nearly all gastrointestinal cancers, from TBRII, TBRI, Smad 2, and Smad 4. Recent exciting data have revealed the role of ELF, a key TGF- 3 pathway adaptor, in hepatocellular cancer suppression. 

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