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Oncogene
open-in-new
<h2 id="history">History</h2> <p>The theory of oncogenes was foreshadowed by the German biologist <a href="/facts/Theodor_Boveri/vMqS6nF4">Theodor Boveri</a> in his 1914 book <i>Zur Frage der Entstehung Maligner Tumoren</i> (Concerning the Origin of Malignant Tumors) in which he predicted the existence of oncogenes <i>(Teilungsfoerdernde Chromosomen)</i> that become amplified <i>(im permanenten Übergewicht)</i> during tumor development.<a class="footnote-ref" id="fnref:14" href="#fn:14"><sup>14</sup></a> </p><p>Later on, the term "oncogene" was rediscovered in 1969 by <a href="/facts/National_Cancer_Institute/R4KbY7Pb">National Cancer Institute</a> scientists George Todaro and <a href="/facts/Robert_Huebner/BLgg71s3">Robert Huebner</a>.<a class="footnote-ref" id="fnref:15" href="#fn:15"><sup>15</sup></a> </p><p>The first confirmed oncogene was discovered in 1970 and was termed <a href="/facts/Proto-oncogene_tyrosine-protein_kinase_Src/5SCJqCU4">SRC</a> (pronounced "sarc" as it is short for sarcoma). SRC was first discovered as an oncogene in a chicken <a href="/facts/Retrovirus/GWAx3C3o">retrovirus</a>. Experiments performed by Dr. G. Steve Martin of the <a href="/facts/University_of_California%2c_Berkeley/MXVEjklr">University of California, Berkeley</a> demonstrated that SRC was indeed the gene of the virus that acted as an oncogene upon infection.<a class="footnote-ref" id="fnref:16" href="#fn:16"><sup>16</sup></a> The first <a href="/facts/Nucleic_acid_sequence/qAf4kTee">nucleotide sequence</a> of <a href="/facts/V-Src/MF1yG8IN">v-Src</a> was <a href="/facts/DNA_sequencing/hsPsNCQW">sequenced</a> in 1980 by A.P. Czernilofsky et al.<a class="footnote-ref" id="fnref:17" href="#fn:17"><sup>17</sup></a> </p><p>In 1976, Drs. Dominique Stéhelin [fr], <a href="/facts/J._Michael_Bishop/mGjgTPJ1">J. Michael Bishop</a> and <a href="/facts/Harold_E._Varmus/PK4lPF5w">Harold E. Varmus</a> of the <a href="/facts/University_of_California%2c_San_Francisco/tPU2yHuW">University of California, San Francisco</a> demonstrated that oncogenes were activated proto-oncogenes as is found in many organisms, including humans. Bishop and Varmus were awarded the <a href="/facts/Nobel_Prize_in_Physiology_or_Medicine/rlnpJX84">Nobel Prize in Physiology or Medicine</a> in 1989 for their discovery of the cellular origin of retroviral oncogenes.<a class="footnote-ref" id="fnref:18" href="#fn:18"><sup>18</sup></a> </p><p>Dr. <a href="/facts/Robert_Weinberg_(biologist)/vX0zYSQy">Robert Weinberg</a> is credited with discovering the first identified human oncogene in a human <a href="/facts/Bladder_cancer/qry4214P">bladder cancer</a> cell line.<a class="footnote-ref" id="fnref:19" href="#fn:19"><sup>19</sup></a><a class="footnote-ref" id="fnref:20" href="#fn:20"><sup>20</sup></a> The molecular nature of the mutation leading to oncogenesis was subsequently isolated and characterized by the Spanish biochemist <a href="/facts/Mariano_Barbacid/rM37BIXo">Mariano Barbacid</a> and published in <i><a href="/facts/Nature_(journal)/XmlJXkFx">Nature</a></i> in 1982.<a class="footnote-ref" id="fnref:21" href="#fn:21"><sup>21</sup></a> Dr. Barbacid spent the following months extending his research, eventually discovering that the oncogene was a mutated <a href="/facts/Allele/8FxCS9KA">allele</a> of <a href="/facts/HRAS/tc0839fm">HRAS</a> and characterizing its activation mechanism. </p><p>The resultant protein encoded by an oncogene is termed oncoprotein.<a class="footnote-ref" id="fnref:22" href="#fn:22"><sup>22</sup></a> 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. </p> <h2 id="proto-oncogene">Proto-oncogene</h2> <p>A proto-oncogene is a normal gene that could become an oncogene due to mutations or increased <a href="/facts/Gene_expression/alCPohLR">expression</a>. Proto-oncogenes code for <a href="/facts/Protein/Jxmagu3E">proteins</a> that help to regulate the <a href="/facts/Cell_growth/wbArMaJU">cell growth</a> and <a href="/facts/Cell_differentiation/bCVqUG7w">differentiation</a>. Proto-oncogenes are often involved in <a href="/facts/Signal_transduction/1bs0Me6w">signal transduction</a> and execution of <a href="/facts/Mitosis/ExxrSUs8">mitogenic</a> signals, usually through their <a href="/facts/Protein/Jxmagu3E">protein</a> products. Upon acquiring an activating mutation, a proto-oncogene becomes a tumor-inducing agent, an oncogene.<a class="footnote-ref" id="fnref:23" href="#fn:23"><sup>23</sup></a> Examples of proto-oncogenes include <a href="/facts/Ras_(protein)/JB883YoM">RAS</a>, <a href="/facts/Wnt_signaling_pathway/7wxpKrjy">WNT</a>, <a href="/facts/Myc/7FGlAtFk">MYC</a>, <a href="/facts/Extracellular_signal-regulated_kinases/NRmUI80z">ERK</a>, and <a href="/facts/Trk_receptor/y2oIVrRx">TRK</a>. The MYC gene is implicated in <a href="/facts/Burkitt%2527s_lymphoma/Ita1VmGg">Burkitt's lymphoma</a>, which starts when a <a href="/facts/Chromosomal_translocation/MKEwqpQw">chromosomal translocation</a> moves an <a href="/facts/Enhancer_sequence/E5NU74sw">enhancer sequence</a> 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 <a href="/facts/Bcr-Abl/YLFIDR3D">Bcr-Abl</a> gene found on the <a href="/facts/Philadelphia_chromosome/YLFIDR3D">Philadelphia chromosome</a>, 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. (More information about the Philadelphia Chromosome below) </p> <h3>Activation</h3> <p>The proto-oncogene can become an oncogene by a relatively small modification of its original function. There are three basic methods of activation: </p> <ol><li>A <a href="/facts/Mutation/Ee4NnWbY">mutation</a> within a proto-oncogene, or within a regulatory region (for example the promoter region), can cause a change in the protein structure, causing <ul><li>an increase in protein (<a href="/facts/Enzyme/DSI1Fh7y">enzyme</a>) activity</li> <li>a loss of <a href="/facts/Regulation_of_gene_expression/9N4G341I">regulation</a></li></ul></li> <li>An increase in the amount of a certain protein (protein concentration), caused by <ul><li>an increase of protein expression (through misregulation)</li> <li>an increase of protein (mRNA) stability, prolonging its existence and thus its activity in the cell</li> <li><a href="/facts/Gene_duplication/CcfJYsDF">gene duplication</a> (one type of <a href="/facts/Chromosome_abnormalities/6hL7p0cP">chromosome abnormality</a>), resulting in an increased amount of protein in the cell</li></ul></li> <li>A <a href="/facts/Chromosomal_translocation/MKEwqpQw">chromosomal translocation</a> (another type of <a href="/facts/Chromosome_abnormalities/6hL7p0cP">chromosome abnormality</a>) <ul><li>There are 2 different types of chromosomal translocations that can occur:</li></ul> <ol><li>translocation events which relocate a proto-oncogene to a new chromosomal site that leads to higher expression</li> <li>translocation events that lead to a fusion between a proto-oncogene and a 2nd gene (this creates a <a href="/facts/Fusion_protein/LCzaDz15">fusion protein</a> with increased cancerous/oncogenic activity) <ul><li>the expression of a constitutively active <i>hybrid protein</i>. This type of mutation in a dividing <a href="/facts/Stem_cell/qgB9dFrI">stem cell</a> in the <a href="/facts/Bone_marrow/4dfudk0H">bone marrow</a> leads to adult <a href="/facts/Leukemia/WpEfW0Qh">leukemia</a></li> <li>Philadelphia Chromosome is an example of this type of translocation event. This chromosome was discovered in 1960 by <a href="/facts/Peter_Nowell/qfmbyQq0">Peter Nowell</a> 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 "<a href="/facts/ABL_(gene)/h9pJd4jf">ABL1</a>" 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 (this activity is due to the "ABL1" half of the protein). 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 (the cell becomes cancerous). As a result, the Philadelphia Chromosome is associated with Chronic Myelogenous Leukemia (as mentioned before) as well as other forms of Leukemia.<a class="footnote-ref" id="fnref:24" href="#fn:24"><sup>24</sup></a></li></ul></li></ol></li></ol> <p>The expression of oncogenes can be regulated by <a href="/facts/MicroRNA/UjqbYYpe">microRNAs</a> (miRNAs), small <a href="/facts/RNA/HxPeNfNj">RNAs</a> 21-25 nucleotides in length that control gene expression by <a href="/facts/Downregulate/6nRoa28r">downregulating</a> them.<a class="footnote-ref" id="fnref:25" href="#fn:25"><sup>25</sup></a> Mutations in such <a href="/facts/MicroRNAs/UjqbYYpe">microRNAs</a> (known as <a href="/facts/Oncomir/XmWc0Gu6">oncomirs</a>) can lead to activation of oncogenes.<a class="footnote-ref" id="fnref:26" href="#fn:26"><sup>26</sup></a> <a href="/facts/Antisense/hcKgNvy6">Antisense</a> messenger RNAs could theoretically be used to block the effects of oncogenes. </p> <h2 id="classification">Classification</h2> <p>There are several systems for classifying oncogenes,<a class="footnote-ref" id="fnref:27" href="#fn:27"><sup>27</sup></a> 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: </p> <table><tbody><tr><th>Category</th><th>Examples</th><th>Cancers</th><th>Gene functions</th></tr><tr><td><a href="/facts/Growth_factor/D1xnRbcH">Growth factors</a>, or mitogens</td><td><a href="/facts/C-Sis/fYpbl1qA">c-Sis</a></td><td><a href="/facts/Glioblastoma/hJojdA5x">glioblastomas</a>, <a href="/facts/Fibrosarcoma/JCBPnCo5">fibrosarcomas</a>, <a href="/facts/Osteosarcoma/FnlFbprC">osteosarcomas</a>, <a href="/facts/Breast_carcinoma/6hME580v">breast carcinomas</a>, and <a href="/facts/Melanoma/qdT7E97Y">melanomas</a><a class="footnote-ref" id="fnref:28" href="#fn:28"><sup>28</sup></a></td><td>induces cell proliferation.</td></tr><tr><td><a href="/facts/Receptor_tyrosine_kinases/1oNWIdV8">Receptor tyrosine kinases</a></td><td><a href="/facts/Epidermal_growth_factor_receptor/NLmnXKYY">epidermal growth factor receptor</a> (EGFR), <a href="/facts/Platelet-derived_growth_factor_receptor/Wmj7CSw1">platelet-derived growth factor receptor</a> (PDGFR), and <a href="/facts/Vascular_endothelial_growth_factor/kNDc0Xj0">vascular endothelial growth factor</a> receptor (VEGFR), <a href="/facts/HER2%2fneu/xue3SgcA">HER2/neu</a></td><td>Breast cancer, gastrointestinal stromal tumours, non-small-cell lung cancer and pancreatic cancer<a class="footnote-ref" id="fnref:29" href="#fn:29"><sup>29</sup></a></td><td>transduce signals for cell growth and differentiation.</td></tr><tr><td>Cytoplasmic <a href="/facts/Tyrosine_kinases/26Ln0qJ4">tyrosine kinases</a></td><td><a href="/facts/Src_(gene)/5SCJqCU4">Src</a>-family, <a href="/facts/Syk-ZAP-70/LIDFqL5K">Syk-ZAP-70</a> family, and <a href="/facts/Bruton%2527s_tyrosine_kinase/6NCNAg20">BTK</a> family of tyrosine kinases, the Abl gene in CML - <a href="/facts/Philadelphia_chromosome/YLFIDR3D">Philadelphia chromosome</a></td><td>colorectal and breast cancers, melanomas, ovarian cancers, gastric cancers, head and neck cancers, pancreatic cancer, lung cancer, brain cancers, and blood cancers<a class="footnote-ref" id="fnref:30" href="#fn:30"><sup>30</sup></a></td><td>mediate the responses to, and the activation receptors of cell proliferation, migration, differentiation, and survival<a class="footnote-ref" id="fnref:31" href="#fn:31"><sup>31</sup></a></td></tr><tr><td>Cytoplasmic <a href="/facts/Serine%2fthreonine_kinases/QKSTb82e">Serine/threonine kinases</a> and their regulatory subunits</td><td><a href="/facts/C-Raf/NvJ0vMl6">Raf kinase</a>, and <a href="/facts/Cyclin-dependent_kinase/ppYkzTaR">cyclin-dependent kinases</a> (through <a href="/facts/Overexpression/N9yVF3lR">overexpression</a>).</td><td>malignant melanoma, papillary thyroid cancer, colorectal cancer, and ovarian cancer<a class="footnote-ref" id="fnref:32" href="#fn:32"><sup>32</sup></a></td><td>involved in organism development, cell cycle regulation, cell proliferation, differentiation, cells survival, and apoptosis<a class="footnote-ref" id="fnref:33" href="#fn:33"><sup>33</sup></a></td></tr><tr><td>Regulatory <a href="/facts/GTPase/74gpHwWI">GTPases</a></td><td><a href="/facts/Ras_protein/JB883YoM">Ras protein</a></td><td>adenocarcinomas of the pancreas and colon, thyroid tumors, and myeloid leukemia<a class="footnote-ref" id="fnref:34" href="#fn:34"><sup>34</sup></a></td><td>involved in signalling a major pathway leading to cell proliferation.<a class="footnote-ref" id="fnref:35" href="#fn:35"><sup>35</sup></a></td></tr><tr><td><a href="/facts/Transcription_factor/wro0DPHe">Transcription factors</a></td><td><a href="/facts/Myc/7FGlAtFk">myc</a> gene</td><td>malignant T-cell lymphomas and acute myeloid leukemias, breast cancer, pancreatic cancer, retinoblastoma, and small cell lung cancer<a class="footnote-ref" id="fnref:36" href="#fn:36"><sup>36</sup></a></td><td>regulate transcription of genes that induce cell proliferation.</td></tr><tr><td><a href="/facts/Coactivator_(genetics)/0lVABmQx">Transcriptional coactivators</a></td><td><a href="/facts/YAP1/jl4okjo9">YAP</a>, <a href="/facts/WWTR1/5HCuCMe8">WWTR1</a> genes</td><td>glioma, melanoma, lung cancer, breast cancers, and more<a class="footnote-ref" id="fnref:37" href="#fn:37"><sup>37</sup></a></td><td>interact with transcription factor partners to regulate transcription of genes that induce cell proliferation.</td></tr></tbody></table> <p>Additional oncogenetic regulator properties include: </p> <ul><li>Growth factors are usually <a href="/facts/Secretion/VHk9eLAV">secreted</a> by either specialized or non-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 (<i><a href="/facts/Autocrine_loop/EwfQEYzG">autocrine loop</a></i>), and proliferation of neighboring cells, possibly leading to tumor formation. It may also cause production of growth hormones in other parts of the body.</li> <li><a href="/facts/Receptor_tyrosine_kinase/1oNWIdV8">Receptor tyrosine kinases</a> add phosphate groups to other proteins in order to turn them on or off. Receptor kinases add phosphate groups to receptor proteins at the surface of the cell (which receives protein signals from outside the cell and transmits 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.</li> <li>Ras is a small GTPase that hydrolyses GTP into GDP and phosphate. Ras is activated by growth factor signaling (i.e., EGF, TGFbeta) and acting as a binary switch (on/off) in growth signaling pathways. Downstream effectors of Ras include three mitogen-activated protein kinases Raf a MAP Kinase Kinase Kinase (MAPKKK), MEK a MAP Kinase Kinase (MAPKK), and ERK a MAP Kinase(MAPK), which in turn regulate genes that mediate cell proliferation.<a class="footnote-ref" id="fnref:38" href="#fn:38"><sup>38</sup></a></li></ul> <h2 id="see-also">See also</h2> <ul><li><a href="/facts/Anticancer_gene/gxoxHJYI">Anticancer gene</a></li> <li><a href="/facts/Oncogenomics/Lf414K3f">Oncogenomics</a></li> <li><a href="/facts/Tumor_suppressor_gene/Awte4S51">Tumor suppressor gene</a></li> <li><a href="/facts/Oncovirus/AHDgPhAn">Oncovirus</a></li> <li><a href="/facts/Genetic_predisposition/rQkzYCYv">Genetic predisposition</a></li> <li><a href="/facts/Quantitative_trait_locus/ztEdNEJg">Quantitative trait locus</a></li> <li><a href="/facts/Public_health_genomics/YJzUXCBK">Genetic susceptibility</a></li> <li><a href="/facts/Oncometabolism/YCTWCJMN">Oncometabolism</a></li></ul> <h2 id="external-links">External links</h2> Wikimedia Commons has media related to Proto-oncogene proteins. <ul><li><a href="http://www.sdbonline.org/fly/aignfam/tumorsup.htm"><i>Drosophila</i> Oncogenes and Tumor Suppressors - The Interactive Fly</a></li></ul> <h2 id="references">References</h2> <ol> <li id="fn:1"><p>Wilbur B, ed. (2009). The World of the Cell (7th ed.). San Francisco, California.{{cite book}}: CS1 maint: location missing publisher (link) <a href="/wiki/Template:Cite_book" target="_blank">/wiki/Template:Cite_book</a> <a href="#fnref:1" class="footnote-back-ref">↩</a></p></li> <li id="fn:2"><p>Kimball's Biology Pages. Archived 2017-12-31 at the Wayback Machine "Oncogenes" Free full text <a href="http://users.rcn.com/jkimball.ma.ultranet/BiologyPages/O/Oncogenes.html" target="_blank">http://users.rcn.com/jkimball.ma.ultranet/BiologyPages/O/Oncogenes.html</a> <a href="#fnref:2" class="footnote-back-ref">↩</a></p></li> <li id="fn:3"><p>The Nobel Prize in Physiology or Medicine 2002. 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