Oncogenes in Human Tumors

Ras genes encode a family of proteins (all of about 21 kilodaltons) with regions homologous to sequences in the subunit of G proteins (see here). Like the subunit, the Ras proteins bind guanine nucleotides. Normal Ras proteins possess a GTPase activity, as do G proteins, whereas most ras oncogene proteins lack this activity (by convention, the name of the gene is italicized, and the corresponding protein is not). The GTPase activity suggested that normal Ras proteins function like G proteins in regulating metabolism. A mutation in the twelfth codon of the human ras oncogene that changes a glycine codon to a valine codon eliminates the protein's ability to hydrolyze GTP to GDP. In 1988, the three-dimensional structure of a Ras protein, crystallized with GDP was determined. Amino acid residues known to be changed in mutations that generate ras oncogenes are positioned close to the bound guanine nucleotide. This positioning supports the idea that interactions between the proto-oncogene Ras protein and guanine nucleotides are important to metabolic control and that this control is lost when a normal cell is transformed to a cancer cell.

A major difference between Ras-type proteins and the related G proteins is the far higher GTPase activity of the G proteins. A set of Ras-activating proteins is required to stimulate the GTPase activity of Ras. G, but not Ras, proteins contain a conserved arginine residue (R178), which stabilizes the negative charge on the phosphate of bound GTP.

Research on oncogenes has led to unifying theories of carcinogenesis. The great majority of chemical carcinogens are also mutagens. Chemical carcinogenesis involves mutagenesis of cellular proto-oncogenes, events that can occur in the absence of exogenous viruses (mechanism 2 in Figure 23.19). Indeed, ras genes altered in codon 12 have been detected in a variety of spontaneous and chemically induced tumors, in both animals and humans.

Other genetic alterations that lead to tumors involve antioncogenes, or tumor suppressor genes. Unlike proto-oncogenes, these are genes that in the normal form suppress cell division. Loss of normal gene function leads to tumor formation. One of these genes is called the retinoblastoma gene. Mutations in the two alleles of this gene cause a type of eye tumor.

The other most prominent tumor suppressor gene encodes a protein called p53 (a protein of 53 kilodaltons). Loss of p53 function leads to tumorigenesis, and a large fraction of human tumors examined display p53 gene mutations. Although all its biochemical actions are not yet clear, p53 is a DNA-binding protein that plays a role in regulating the cell cycle, preventing inappropriate movement of G1 cells into S phase. Loss of such a checkpoint could result in the loss of cell growth control associated with cancer.

Binding to specific DNA sequences is essential for the proper functioning of p53. This was revealed in 1994 when the structure of the DNA-binding domain in contact with an oligonucleotide containing the binding sequence was determined by x-ray crystallography. Of great interest is that the amino acid residues in closest contact with DNA are those that have been shown most often to be changed in p53 mutant genes isolated from human tumors.

About a dozen antioncogenes had been identified. Mutations affecting most of these genes have been detected in the germ line of human cells and have been correlated with the predisposition to become afflicted with certain forms of cancer.

See also: Viral and Cellular Oncogenes, Oncogenes and Cell Signalling, G Proteins and Signal Transduction, G Protein Families and Subunits

INTERNET LINKS:

> 1. p53 Tumor Suppressor Protein

> 2. Tumor Suppressor Genes

> 3. Tumor Suppressor Genes and Cancer Treatment