Oncogene

An oncogene is a protein encoding gene which, when deregulated, participates in the onset and development of cancer. Genetic mutations resulting in the activation of oncogenes increase the chance that a normal cell will develop into a tumor cell. Oncogenes are figuratively thought to be in a perpetual tug-of-war with tumor suppressor genes which act to prevent DNA damage and keep the cell's activities under control. There is much evidence to support the notion that loss of tumor suppressors or gain of oncogenes can lead to cancer.

Many cells normally undergo an apoptosis program. In the presence of an activated oncogene, disorderly survival and proliferation can be observed.^[1] 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 new cancer drugs target those DNA sequences and their products.^[2]^[3]^[4]

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.^[5] 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:

Mutations in microRNAs can lead to activation of oncogenes.^[6] New research indicates that small RNAs 21-25 nucleotides in length called microRNAs (miRNAs) can control expression of these genes by downregulating them.^[7]

Classification

There are several systems for classifying oncogenes,^[8]^[9] 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

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 responsible for the acquisition of the new properties.^[10]

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.

Oncogene

Contents

Proto-oncogene

Activation

Classification

Conversion of proto-oncogenes

History

See also

References