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From Wikipedia, the free encyclopedia

An oncogene is a gene that, when mutated or expressed at high levels, helps turn a normal cell into a tumor cell.[1]

Many abnormal cells normally undergo a programmed form of death (apoptosis). Activated oncogenes can cause those cells to survive and proliferate instead.[2] 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 those DNA sequences and their products.[3][4][5][6]

Contents

Proto-oncogene

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.[7] Examples of proto-oncogenes include RAS, WNT, MYC, ERK, and TRK.

Activation

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
    • an increased gene expression in the wrong cell type or at wrong times
    • the expression of a constitutively active hybrid protein. This type of aberration in a dividing stem cell in the bone marrow leads to adult leukemia

Mutations in microRNAs can lead to activation of oncogenes.[8] New research indicates that small RNAs 21-25 nucleotides in length called microRNAs (miRNAs) can control expression of these genes by downregulating them.[9]Antisense messenger RNAs could theoretically be used to block the effects of oncogenes.

Classification

There are several systems for classifying oncogenes,[10][11] 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 which hydrolyses GTP into GDP and phosphate. Ras is activated by growth factor signaling (ie. 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 -

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 which are responsible for the acquisition of the new properties.[12]

History

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.

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.[13]

See also

References

  1. ^ Kimball's Biology Pages. "Oncogenes" Free full text
  2. ^ The Nobel Prize in Physiology or Medicine 2002. Illustrated presentation.
  3. ^ Kimball's Biology Pages. "Oncogenes" Free full text
  4. ^ Croce CM (Jan 2008). "Oncogenes and cancer". N Engl J Med. 358 (5): 502–11. doi:10.1056/NEJMra072367. PMID 18234754. http://content.nejm.org/cgi/content/full/358/5/502.  
  5. ^ Yokota J (Mar 2000). "Tumor progression and metastasis". Carcinogenesis. 21 (3): 497–503. doi:10.1093/carcin/21.3.497. PMID 10688870. http://carcin.oxfordjournals.org/cgi/content/full/21/3/497.  
  6. ^ 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".
  7. ^ Todd R, Wong DT (1999). "Oncogenes". Anticancer Res. 19 (6A): 4729–46. PMID 10697588.  
  8. ^ Esquela-Kerscher A, Slack FJ (Apr 2006). "Oncomirs - microRNAs with a role in cancer". Nat Rev Cancer 6 (4): 259–69. doi:10.1038/nrc1840. PMID 16557279.  
  9. ^ 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.  
  10. ^ THE Medical Biochemistry Page
  11. ^ Classification of Oncogene Function
  12. ^ 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.  
  13. ^ 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.







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