An oncogene is a gene that has the potential to cause cancer. In tumor cells, they are often mutated or expressed at high levels. An oncogene is a gene found in the chromosomes of tumor cells whose activation is associated with the initial and continuing conversion of normal cells into cancer cells.
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. 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.
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. 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. 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:
- A mutation within a proto-oncogene can cause a change in the protein structure, causing
- An increase in protein concentration, caused by
- an increase of protein expression (through misregulation)
- an increase of protein (mRNA) stability, prolonging its existence and thus its activity in the cell
- a gene duplication (one type of chromosome abnormality), resulting in an increased amount of protein in the cell
- A chromosomal translocation (another type of chromosome abnormality), causing
The expression of oncogenes can be regulated by microRNAs (miRNAs), small RNAs 21-25 nucleotides in length that control gene expression by downregulating them. Mutations in such microRNAs (known as oncomirs) can lead to activation of oncogenes. Antisense messenger RNAs could theoretically be used to block the effects of oncogenes.
There are several systems for classifying oncogenes, 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.
Conversion of proto-oncogenes
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.
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.
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- ^ a b Kimball's Biology Pages. "Oncogenes" Free full text
- ^ The Nobel Prize in Physiology or Medicine 2002. Illustrated presentation.
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- ^ The Nobel Prize in Physiology or Medicine 1989 to J. Michael Bishop and Harold E. Varmus for their discovery of "the cellular origin of retroviral oncogenes".
- ^ Chapter 20 - NEOPLASMS OF THE THYROID - in: Mitchell, Richard Sheppard; Kumar, Vinay; Abbas, Abul K.; Fausto, Nelson. Robbins Basic Pathology. Philadelphia: Saunders. ISBN 1-4160-2973-7. 8th edition.
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- ^ Negrini M, Ferracin M, Sabbioni S, Croce CM (Jun 2007). "MicroRNAs in human cancer: from research to therapy". J Cell Sci. 120 (Pt 11): 1833–40. doi:10.1242/jcs.03450. PMID 17515481.
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- ^ THE Medical Biochemistry Page
- ^ Classification of Oncogene Function
- ^ Emery, Alan E. H.; Mueller, Robert Francis; Young, Ian T.; Ian D., MD Young (2001). "Oncogene". Emery's elements of medical genetics. Edinburgh: Churchill Livingstone. ISBN 0-443-07125-X.
- ^ Nobel Prize in Physiology or Medicine for 1989 jointly to J. Michael Bishop and Harold E. Varmus for their discovery of "the cellular origin of retroviral oncogenes". Press Release.
- Drosophila Oncogenes and Tumor Suppressors - The Interactive Fly
- List of web sites - oncogenes tables
Pathology: Tumor, Neoplasm, Cancer, and Oncology (C00–D48, 140–239) ConditionsMalignant progressionTopographyHistologyOtherPrecancerous condition · Paraneoplastic syndrome Staging/grading Carcinogenesis Misc.
tumr, epon, para
Neoplasm: Tumor suppressor genes/proteins and Oncogenes/Proto-oncogenes Ligand ReceptorTSP: CDH1TSP: PTCH1TSP: TGF beta receptor 2 Intracellular signaling P+PsONCO: Beta-catenin · TSP: APCHippo signaling pathwayOther/unknown NucleusTSP: VHL · ONCO: CBL - MDM2 Mitochondria Other/ungrouped
tumr, epon, para
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oncogene — oncogene. См. онкоген. (Источник: «Англо русский толковый словарь генетических терминов». Арефьев В.А., Лисовенко Л.А., Москва: Изд во ВНИРО, 1995 г.) … Молекулярная биология и генетика. Толковый словарь.
oncogene — (n.) 1969, from ONCO (Cf. onco ) + gene, from root of Gk. gignere (perf. genui) beget, from PIE *gen produce (see GENUS (Cf. genus)) … Etymology dictionary
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oncogene — /ong keuh jeen /, n. Genetics. any gene that is a causative factor in the initiation of cancerous growth. [1965 70; ONCO + GENE] * * * Gene that can cause cancer. It is a sequence of DNA that has been altered or mutated from its original form,… … Universalium
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