Oncogene


Oncogene

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] 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.[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]

Contents

Proto-oncogene

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.

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

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.

Classification

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.

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.[13]

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. 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]

See also

References

  1. ^ Wilbur, Beth, editor. The World of the Cell, Becker, W.M., et al., 7th ed. San Francisco, CA; 2009.
  2. ^ a b Kimball's Biology Pages. "Oncogenes" Free full text
  3. ^ The Nobel Prize in Physiology or Medicine 2002. Illustrated presentation.
  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. ^ 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.
  8. ^ Todd R, Wong DT (1999). "Oncogenes". Anticancer Res. 19 (6A): 4729–46. PMID 10697588. 
  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. ^ 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. 
  11. ^ THE Medical Biochemistry Page
  12. ^ Classification of Oncogene Function
  13. ^ 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. 
  14. ^ 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.

External links


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Look at other dictionaries:

  • oncogène — [ ɔ̃kɔʒɛn ] adj. • 1951; du gr. onkos « grosseur, tumeur » et gène ♦ Didact. Qui favorise le développement des tumeurs, notamment des tumeurs malignes (⇒ cancérigène). Virus oncogène. Gène oncogène ou n. m. un oncogène : gène, souvent porté par… …   Encyclopédie Universelle

  • 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

  • oncogene — ☆ oncogene [äŋ′kə jēn΄ ] n. [< Gr onkos, mass + GENE] any of various genes that, when activated as by radiation or a virus, may cause a normal cell to become cancerous oncogenic [äŋ′kəjen′ik] adj …   English World dictionary

  • Oncogène — Les oncogènes sont une catégorie de gènes dont l expression favorise la survenue de cancers. Ce sont des gènes qui commandent la synthèse d oncoprotéines (protéines anormales stimulant la division et la différenciation cellulaire) et déclenchent… …   Wikipédia en Français

  • 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

  • oncogene — A gene that causes cells to grow in an uncontrolled (i.e. tumourous) manner. Oncogenes are mutant forms of normal functional genes (called proto oncogenes) that have a role in regulating cell proliferation. See: cellular oncogene; dominant… …   Glossary of Biotechnology

  • Oncogene — Cette page d’homonymie répertorie les différents sujets et articles partageant un même nom. Sur les autres projets Wikimedia : « oncogène », sur le Wiktionnaire (dictionnaire universel) Les oncogènes, une catégorie de gènes… …   Wikipédia en Français

  • oncogene — 1. Any of a family of genes that normally encode proteins involved in cell growth or regulation (e.g., protein kinases, GTPases, nuclear proteins, growth factors) but that may foster malignant processes if mutated or activated by contact with… …   Medical dictionary

  • oncogene — Mutated and/or overexpressed version of a normal gene of animal cells (the proto oncogene) that in a dominant fashion can release the cell from normal restraints on growth, and thus alone, or in concert with other changes, convert a cell into a… …   Dictionary of molecular biology


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