An oncogene is a gene that has the potential to cause cancer.[1] In tumor cells, they are often mutated or expressed at high levels.[2]
Most normal cells undergo a programmed form of death (apoptosis). Activated oncogenes can cause those cells that ought to die to survive and proliferate instead.[3] Most oncogenes require an additional step, such as mutations in another gene, or environmental factors, such as viral infection, to cause cancer. Since the 1970s, dozens of oncogenes have been identified in human cancer. Many cancer drugs target the proteins encoded by oncogenes.[2][4][5][6]
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A proto-oncogene is a normal gene that can become an oncogene due to mutations or increased expression. The resultant protein may be termed an oncoprotein.[7] Proto-oncogenes code for proteins that help to regulate cell growth and differentiation. Proto-oncogenes are often involved in signal transduction and execution of mitogenic signals, usually through their protein products. Upon activation, a proto-oncogene (or its product) becomes a tumor-inducing agent, an oncogene.[8] 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 receptor tyrosine kinase, which is constitutively active, leading to uncontrolled cell proliferation.
The proto-oncogene can become an oncogene by a relatively small modification of its original function. There are three basic activation types:
The expression of oncogenes can be regulated by microRNAs (miRNAs), small RNAs 21-25 nucleotides in length that control gene expression by downregulating them.[9] Mutations in such microRNAs (known as oncomirs) can lead to activation of oncogenes.[10] Antisense messenger RNAs could theoretically be used to block the effects of oncogenes.
There are several systems for classifying oncogenes,[11][12] but there is not yet a widely accepted standard. They are sometimes grouped both spatially (moving from outside the cell inwards) and chronologically (parallelling the "normal" process of signal transduction). There are several categories that are commonly used:
| Category | Examples | Description |
| Growth factors, or mitogens | c-Sis | Usually secreted by specialized cells to induce cell proliferation in themselves, nearby cells, or distant cells. An oncogene may cause a cell to secrete growth factors even though it does not normally do so. It will thereby induce its own uncontrolled proliferation (autocrine loop), and proliferation of neighboring cells. It may also cause production of growth hormones in other parts of the body. |
| Receptor tyrosine kinases | epidermal growth factor receptor (EGFR), platelet-derived growth factor receptor (PDGFR), and vascular endothelial growth factor receptor (VEGFR), HER2/neu | Kinases add phosphate groups to other proteins to turn them on or off. Receptor kinases add phosphate groups to receptor proteins at the surface of the cell (which receive protein signals from outside the cell and transmit them to the inside of the cell). Tyrosine kinases add phosphate groups to the amino acid tyrosine in the target protein. They can cause cancer by turning the receptor permanently on (constitutively), even without signals from outside the cell. |
| Cytoplasmic tyrosine kinases | Src-family, Syk-ZAP-70 family, and BTK family of tyrosine kinases, the Abl gene in CML - Philadelphia chromosome | - |
| Cytoplasmic Serine/threonine kinases and their regulatory subunits | Raf kinase, and cyclin-dependent kinases (through overexpression). | - |
| Regulatory GTPases | Ras protein | Ras is a small GTPase that hydrolyses GTP into GDP and phosphate. Ras is activated by growth factor signaling (i.e., EGF, TGFalpha) and acting like a binary switch (on/off) in growth signaling pathways. Downstream effectors of Ras include Raf, MEK, MEKK, MAPK, ERK, most of which in turn regulate genes that mediate cell proliferation. |
| Transcription factors | myc gene | -They regulate transcription of genes that induce cell proliferation. |
There are two mechanisms by which proto-oncogenes can be converted to cellular oncogenes:
Quantitative: Tumor formation is induced by an increase in the absolute number of proto-oncogene products or by its production in inappropriate cell types.
Qualitative: Conversion from proto-oncogene to transforming gene (c-onc) with changes in the nucleotide sequence that are responsible for the acquisition of the new properties.[13]
The first oncogene was discovered in 1970 and was termed src (pronounced sarc as in sarcoma). Src was in fact first discovered as an oncogene in a chicken retrovirus. Experiments performed by Dr G. Steve Martin of the University of California, Berkeley demonstrated that the SRC was indeed the oncogene of the virus. The first nucleotide sequence of v-src was sequenced 1980 by A.P. Czernilofsky et al. (Nature Vol 287, pp 198-203).
In 1976 Drs. Dominique Stehelin, 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. For this discovery Bishop and Varmus were awarded the Nobel Prize in Physiology or Medicine in 1989.[14]
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