Tumor Suppressor Genes
Although the activation of protooncogenes can be accomplished by a number of different molecular mechanisms, it should be pointed out that onset of cancer can be controlled genetically at a higher level. Tumor suppressor genes have been detected in the human genome that prevent the onset of cancer even if one of the above molecular events does occur. These genes have been very difficult to isolate and analyze, but recent evidence suggests several functions.
Retinoblastoma is a juvenile eye cancer that is caused by a mutation in the Rb gene located on chromosome 13 of humans. This gene suppresses the development of cancer as its dominant phenotype. Therefore both alleles must be mutant for the disease to develop. The Rb gene product interacts with a protein called E2F, nuclear transcription factor involved in cellular replication functions during the S phase of the cell cycle. By interacting with E2F it prevents it this function. The Rb gene product is only active when it is not phosphorylated by a kinase. It can not interact with E2F when it is phosphorylated. The mutant Rb gene product is always phosphorylated and can not regulate E2F, control of cell division at the S phase does not occur, and normal cells become cancerous.
p53, located human chromosome 17, is another gene with tumor suppressor activities. This protein contains 393 amino acids and a single amino acid substitution can lead to loss of function of the gene. Mutations at amino acids 175, 248, and 273 can lead to loss of function and changes at 273 (13%) are the most common. These all act as recessive mutations. Dominant gain-of-function mutations have also been found that lead to uncontrolled cell division. Because these mutations can be expressed in heterozygous conditions, they are often associated with cancers. This genetic function of this gene is to prevent cell division of cells with damaged DNA. Damaged DNA could contain genetic changes that promote uncontrolled cell growth. Therefore, preventing cell division until damaged DNA is repaired is one mechanism of preventing the onset of cancer. About 50% of human cancers can be associated with a p53 mutation including cancers of the bladder, breast, cervix, colon, lung, liver, prostate, and skin. p53 related cancers are also more aggressive and have a higher degree of fatalities.
Copyright © 1997. Phillip McClean