Proto-oncogenes are functional structural genes present in the human genome that have sequences very similar to oncogenes seen in viruses. Under normal conditions, the proto-oncogenes perform vital functions in the cell. They have been shown to be associated with control of cell growth, differentiation, and proliferation including regulation of secreted growth factors, cell surface receptors, signal transduction systems, transcription factors, and the cell cycle.
However, proto-oncogenes can be altered to an oncogenic form by mutation. This most commonly occurs by chromosomal rearrangement, usually a translocation, although point mutations and gene amplification have also been reported. Once transformed, or activated, the proto-oncogene loses its normal function causing a disruption in cell regulation patterns, and potentially leading to carcinogenesis. Each proto-oncogene appears to have a unique mutation that causes this change in state, i.e., every time a particular proto-oncogene is modified to the oncogenic form, the same mutation must occur. nly a single mutation in one of a pair of proto-oncogenes is necessary for disease to occur, so the resultant disease is considered to be dominant.
The first chromosome rearrangement involving a proto-oncogene was detected in chronic myelogenous leukemia (CML). The proto-oncogene c-abl is located on chromosome 9 and produces a tyrosine kinase necessary for cellular function. The gene is feedback inhibited such that only the amount of enzyme that can be utilized by the cell is normally produced. A translocation between c-abl and another protein kinase gene on chromosome 22 creates a structurally abnormal chromosome 22 known as the Philadelphia chromosome (Ph'; named for the city in which it was identified). Biochemically, there is a change to constitutive synthesis of tyrosine kinase resulting in an overproduction of the enzyme, and this has been directly correlated with the disease CML. In cell lines, if the translocation is repaired and the excess of tyrosine kinase removed, the cells will revert to their normal state. eintroduction of the translocation once again causes the cells to express a cancer phenotype.
Over 50 proto-oncogenes have been identified in mammalian systems. Since the c-abl rearrangement was first described, additional similar proto-oncogene translocations have been identified that give rise to a variety of other leukemias and lymphomas. Mutations in proto-oncogenes have also been shown to be involved in solid tumor formation. Fortunately, many checks and balances exist within cells to protect against high levels of mutation, and since the mutation events that transform the proto-oncogenes are highly specific, cases of cancer are relatively rare events. However, it is known that this type of mutation can be influenced by environmental factors, so, as with tumor suppressor genes, within a given population, some individuals will have a higher risk of disease than others.
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