An oncogene is a gene that has the potential to cause cancer. In tumor cells, these genes are often mutated, or expressed at high levels. Most normal cells will undergo a programmed form of rapid cell death when critical functions are altered and malfunctioning. Activated oncogenes can cause those cells designated for apoptosis to survive and proliferate instead. Most oncogenes began as proto-oncogenes: normal genes involved in cell growth and proliferation or inhibition of apoptosis. If, through mutation, normal genes promoting cellular growth are up-regulated, they will predispose the cell to cancer; thus, they are termed "oncogenes". Usually multiple oncogenes, along with mutated apoptotic or tumor suppressor genes will all act in concert to cause cancer. Since the 1970s, dozens of oncogenes have been identified in human cancer. Many cancer drugs target the proteins encoded by oncogenes.
History
The theory of oncogenes was foreshadowed by the German biologist Theodor Boveri in his 1914 book Zur Frage der Entstehung Maligner Tumoren in which he predicted the existence of oncogenes ' that become amplified ' during tumor development. Later on the term "oncogene" was rediscovered in 1969 by National Cancer Institute scientists George Todaro and Robert Huebner. The first confirmed oncogene was discovered in 1970 and was termed SRC. SRC was first discovered as an oncogene in a chicken retrovirus. Experiments performed by Dr. G. Steve Martin of the University of California, Berkeley demonstrated that SRC was indeed the gene of the virus that acted as an oncogene upon infection. The first nucleotide sequence of v-Src was sequenced in 1980 by A.P. Czernilofsky et al. In 1976, Drs., J. Michael Bishop and Harold E. Varmus of the University of California, San Francisco demonstrated that oncogenes were activated proto-oncogenes, found in many organisms including humans. Bishop and Varmus were awarded the Nobel Prize in Physiology or Medicine in 1989 for their discovery of the cellular origin of retroviral oncogenes. Dr. Robert Weinberg is credited with discovering the first identified human oncogene in a human bladder cancer cell line. The molecular nature of the mutation leading to oncogenesis was subsequently isolated and characterized by the Spanish biochemist Mariano Barbacid and published in Nature in 1982. Dr. Barbacid spent the following months extending his research, eventually discovering that the oncogene was a mutated allele of HRAS and characterizing its activation mechanism. The resultant protein encoded by an oncogene is termed oncoprotein. Oncogenes play an important role in the regulation or synthesis of proteins linked to tumorigenic cell growth. Some oncoproteins are accepted and used as tumor markers.
Proto-oncogene
A proto-oncogene is a normal gene that could become an oncogene due to mutations or increased expression. Proto-oncogenes code for proteins that help to regulate the cell growth and differentiation. Proto-oncogenes are often involved in signal transduction and execution of mitogenic signals, usually through their protein products. Upon acquiring an activating mutation, a proto-oncogene becomes a tumor-inducing agent, an oncogene. Examples of proto-oncogenes include RAS, WNT, MYC, ERK, and TRK. The MYC gene is implicated in Burkitt's lymphoma, which starts when a chromosomal translocation moves an enhancer sequence within the vicinity of the MYC gene. The MYC gene codes for widely used transcription factors. When the enhancer sequence is wrongly placed, these transcription factors are produced at much higher rates. Another example of an oncogene is the Bcr-Abl gene found on the Philadelphia chromosome, a piece of genetic material seen in Chronic Myelogenous Leukemia caused by the translocation of pieces from chromosomes 9 and 22. Bcr-Abl codes for a tyrosine kinase, which is constitutively active, leading to uncontrolled cell proliferation.
Activation
The proto-oncogene can become an oncogene by a relatively small modification of its original function. There are three basic methods of activation:
#translocation events which relocate a proto-oncogene to a new chromosomal site that leads to higher expression
#translocation events that lead to a fusion between a proto-oncogene and a 2nd gene
#* the expression of a constitutively active hybrid protein. This type of mutation in a dividing stem cell in the bone marrow leads to adult leukemia
#*Philadelphia Chromosome is an example of this type of translocation event. This chromosome was discovered in 1960 by Peter Nowell and David Hungerford, and it is a fusion of parts of DNA from chromosome 22 and chromosome 9. The broken end of chromosome 22 contains the "BCR" gene, which fuses with a fragment of chromosome 9 that contains the "ABL1" gene. When these two chromosome fragments fuse the genes also fuse creating a new gene: "BCR-ABL". This fused gene encodes for a protein that displays high protein tyrosine kinase activity. The unregulated expression of this protein activates other proteins that are involved in cell cycle and cell division which can cause a cell to grow and divide uncontrollably. As a result, the Philadelphia Chromosome is associated with Chronic Myelogenous Leukemia as well as other forms of Leukemia.
The expression of oncogenes can be regulated by microRNAs, small RNAs 21-25 nucleotides in length that control gene expression by downregulating them. Mutations in such microRNAs can lead to activation of oncogenes. Antisense messenger RNAs could theoretically be used to block the effects of oncogenes.
Classification
There are several systems for classifying oncogenes, but there is not yet a widely accepted standard. They are sometimes grouped both spatially and chronologically. There are several categories that are commonly used: Additional oncogenetic regulator properties include:
