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An oncogene is a gene with a DNA sequence that causes cancer.
Many cells are normally destined to die. In cancer, because of that DNA sequence, those cells survive and proliferate.The Nobel Prize in Physiology or Medicine 2002. Illustrated presentation. Most oncogenes require an additional step, such as mutations in another gene, or environmental factors such as viral infection, to cause cancer. Since the 1980s, dozens of oncogenes have been identified in human cancer. Many new cancer drugs target those DNA sequences and their products.Kimball\'s Biology Pages. "Oncogenes" Free full textCroce CM, Oncogenes and Cancer, N Engl J Med 2008, 358:502-511 Free full textYokota J (2000 Mar). ""Tumor progression and metastasis"". Carcinogenesis. 21 (3): 497-503. Free full text
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A proto-oncogene is a normal gene that can become an oncogene due to mutations or increased expression. 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.Todd R, Wong DT (1999). ""Oncogenes"". Anticancer Res. 19 (6A): 4729-46. Examples of proto-oncogenes include RAS, WNT, MYC, ERK and TRK.
The proto-oncogene can become an oncogene by a relatively small modification of its original function. There are three basic activation types:
Mutations in microRNAs can lead to activation of oncogenes.Esquela-Kerscher, A; Slack FJ (Apr 2006). "Oncomirs - microRNAs with a role in cancer". Nature Reviews Cancer 6 (4): 259-269. New research indicates that small RNAs 21-25 nucleotides in length called microRNAs (miRNAs) can control expression of these genes by downregulating them.Negrini, M; Ferracin M, Sabbioni S, Croce CM (Jun 2007). "MicroRNAs in human cancer: from research to therapy". Journal of Cell Science 120 (11): 1833-1840.
There are several systems for classifying oncogenes,THE Medical Biochemistry PageClassification of Oncogene Function 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 | - |
| Transcription factors | myc gene | - |
The first oncogene was discovered in 1970 and was termed src (pronounced SARK). 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.
In 1976 Drs. J. Michael Bishop and Harold E. Varmus of the University of California, San Francisco demonstrated that oncogenes were defective proto-oncogenes, found in many organisms including humans. For this discovery Bishop and Varmus were awarded the Nobel Prize in 1989.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.
| Oncogenes/Proto-oncogenes | |
|---|---|
| Transcription factors | AP-1 (c-Fos, c-Jun) - c-Myc |
| Tyrosine kinase / Receptors | c-ErbB (HER2/neu, Her 3) - c-Kit - c-Met - c-Ret - Flt3 - |
| Other | c-Akt - c-Bcl-2 - c-Mdm2 - -c-Raf - c-Ras (HRAS) - c-Sis - c-Src - Notch - Stathmin |
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