Oncogene

What are Oncogenes?

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

Many abnormal cells normally undergo a programmed form of death (apoptosis). Activated oncogenes can cause those cells 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 those DNA sequences and their products.

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 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 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.

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What are Proto-Oncogenes?

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. 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 (enzyme) activity
    • a loss of regulation
    • 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. New research indicates that small RNAs 21-25 nucleotides in length called microRNAs (miRNAs) can control expression of these genes by downregulating them.Antisense messenger RNAs could theoretically be used to block the effects of oncogenes.

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Oncogene Classification

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:

CategoryExamplesDescription
Growth factors, or mitogensc-SisUsually 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 kinasesepidermal growth factor receptor (EGFR), platelet-derived growth factor receptor (PDGFR), and vascular endothelial growth factor receptor (VEGFR), HER2/neuKinases 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 kinasesSrc-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 subunitsRaf kinase, and cyclin-dependent kinases (through overexpression).-
Regulatory GTPasesRas proteinRas 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 factorsmyc gene-

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