Oncogene

For the journal, see Oncogene (journal).

proto-oncogenes, found in many organisms including huAn oncogene is a gene that has the potential to cause mans. For this discovery, proving Todaro and Heubners
oncogene theory, Bishop and Varmus were awarded the
Nobel Prize in Physiology or Medicine in 1989.[10]
Oncoproteins are any proteins coded by an oncogene and
they play an important role in the regulation or synthesis of proteins linked to tumorigenic cell growth. Some
oncoproteins are accepted and used as tumor markers

2 Proto-oncogene
A proto-oncogene is a normal gene that can become
an oncogene due to mutations or increased expression.
The resultant protein encoded by an oncogene is termed
oncoprotein.[11] Proto-oncogenes code for proteins that
help to regulate cell growth and dierentiation. Protooncogenes 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.[12] Examples of proto-oncogenes include RAS,
WNT, MYC, ERK, and TRK. The MYC gene is implicated in Burkitts 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. BcrAbl codes for a receptor tyrosine kinase, which is constitutively active, leading to uncontrolled cell proliferation.
(More information about the Philadelphia Chromosome
below)

Illustration of how a normal cell is converted to a cancer cell,

when an oncogene becomes activated

cancer.[1] In tumor cells, they are often mutated or expressed at high levels.[2]
Most normal cells will undergo a programmed form of
rapid cell death (apoptosis) when critical functions are
altered. Activated oncogenes can cause those cells designated for apoptosis 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 identied in human cancer. Many cancer drugs target the proteins encoded by
oncogenes.[2][4][5][6]

History

The term oncogene was coined in 1969 by National

Cancer Institute scientists, George Todaro and Robert
Heubner.[7]
The rst conrmed oncogene was discovered in 1970 and
was termed src (pronounced sarc as in sarcoma). Src
was in fact rst 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.[8] The
rst nucleotide sequence of v-src was sequenced in 1980
by A.P. Czernilofsky et al.[9]

2.1 Activation
The proto-oncogene can become an oncogene by a relatively small modication of its original function. There
are three basic methods of activation:
1. A mutation within a proto-oncogene, or within a regulatory region (for example the promoter region),
can cause a change in the protein structure, causing

In 1976 Drs. Dominique Stehelin, J. Michael Bishop and

Harold E. Varmus of the University of California, San
Francisco demonstrated that oncogenes were activated

an increase in protein (enzyme) activity

1

3
proto-oncogene

deletion or point mutation

in coding sequence

gene amplication

chromosome rearrangement
or

DNA
RNA

a hypeactive protein
is produced
in normal amounts

a normal protein
is overexpressed

(A)

(B)

nearby regulatory
fusion to actively
sequence causes
transcribed gene
normal protein
overexpresses
to be overexpressed
fusion protein;
or fusion protein
is hyperactive
(C1)

(C2)

From proto-oncogene to oncogene

CLASSIFICATION

of the protein). The unregulated expression of this protein activates other proteins that are involved in cell cycle and
cell division which can cause a cell to
grow and divide uncontrollably (the cell
becomes cancerous). As a result, the
Philadelphia Chromosome is associated
with Chronic Myelogenous Leukemia (as
mentioned before) as well as other forms
of Leukemia.[13]

The expression of oncogenes can be regulated by

microRNAs (miRNAs), small RNAs 21-25 nucleotides
2. An increase in the amount of a certain protein (pro- in length that control gene expression by downregulating
them.[14] Mutations in such microRNAs (known as
tein concentration), caused by
oncomirs) can lead to activation of oncogenes.[15]
an increase of protein expression (through Antisense messenger RNAs could theoretically be used
misregulation)
to block the eects of oncogenes.
a loss of regulation

an increase of protein (mRNA) stability, prolonging its existence and thus its activity in the
cell

3 Classication

gene duplication (one type of chromosome abare

several
systems
for
classifying
normality), resulting in an increased amount of There
[16][17]
oncogenes,
but
there
is
not
yet
a
widely
acprotein in the cell
cepted standard. They are sometimes grouped both
3. A chromosomal translocation (another type of spatially (moving from outside the cell inwards) and
chronologically (parallelling the normal process of
chromosome abnormality)
signal transduction). There are several categories that
There are 2 dierent types of chromosomal are commonly used:
translocations that can occur:
More detailed information for the above Table:
(a) translocation events which relocate a protooncogene to a new chromosomal site that leads
to higher expression
(b) translocation events that lead to a fusion between a proto-oncogene and a 2nd gene (this
creates a fusion protein with increased cancerous/oncogenic activity)
the expression of a constitutively active
hybrid protein. This type of mutation in
a dividing stem cell in the bone marrow
leads to adult leukemia
Philadelphia Chromosome is an example
of this type of translocation event. This
chromosome was discovered in 1960 by
Peter Nowell and David Hungerford, and
it is a fusion of parts of DNA from chromosome 22 and chromosome 9. The broken end of chromosome 22 contains the
BCR gene, which fuses with a fragment of chromosome 9 that contains the
"ABL1" gene. When these two chromosome fragments fuse the genes also fuse
creating a new gene: BCR-ABL. This
fused gene encodes for a protein that displays high protein tyrosine kinase activity
(this activity is due to the ABL1 half

Growth factors are usually

secreted by either specialized
or not 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 add
phosphate groups to other proteins to turn them on or o.
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

3
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.
Ras is a small GTPase that
hydrolyses GTP into GDP
and phosphate. Ras is activated by growth factor signaling (i.e., EGF, TGFbeta)
and acting like a binary switch
(on/o) in growth signaling
pathways. Downstream effectors of Ras include three
mitogen-activated protein kinases Raf a MAP Kinase
Kinase Kinase (MAPKKK),
MEK a MAP Kinase Kinase
(MAPKK), and ERK a MAP
Kinase(MAPK), which in turn
regulate genes that mediate
cell proliferation.

See also
Oncogenomics
Tumor suppressor gene
Oncovirus
Genetic predisposition
Quantitative trait locus
Genetic susceptibility

References

[1] Wilbur, Beth, editor. The World of the Cell, Becker,

W.M., et al., 7th ed. San Francisco, CA; 2009.
[2] Kimballs 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): 50211. doi:10.1056/NEJMra072367.
PMID 18234754.
[5] Yokota J (Mar 2000).
Tumor progression and
Carcinogenesis.
21 (3): 497503.
metastasis.
doi:10.1093/carcin/21.3.497. PMID 10688870.
[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] The Emperor of All Maladies, Siddhartha Mukherjee,

2011, p. 363, endnote.
[8] The Hunting of the Src, G. Steven Martin, Nature Reviews
Molecular Cell Biology 2: 467 (2001)
[9] (A.P. Czernilofsky et al., 1980, Nature Vol 287, pp 198203).
[10] 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.
[11] 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.
[12] Todd R, Wong DT; Wong (1999). Oncogenes. Anticancer Res. 19 (6A): 472946. PMID 10697588.
[13] Chial, H (2008). Proto-oncogenes to Oncogenes to Cancer. Nature Education 1 (1).
[14] Negrini M, Ferracin M, Sabbioni S, Croce CM; Ferracin;
Sabbioni; Croce (Jun 2007). MicroRNAs in human cancer: from research to therapy. J Cell Sci. 120 (Pt 11):
183340. doi:10.1242/jcs.03450. PMID 17515481.
[15] Esquela-Kerscher A, Slack FJ; Slack (Apr 2006). Oncomirs - microRNAs with a role in cancer. Nat Rev
Cancer 6 (4): 25969. doi:10.1038/nrc1840. PMID
16557279.
[16] THE Medical Biochemistry Page
[17] Classication of Oncogene Function
[18] Press, Richard; Anita Misra; Glenda Gillaspy; David
Samols; David A. Goldthwait2 (June 1, 1989). Control
of the Expression of c-sis mRNA in Human Glioblastoma
Cells by Phorbol Ester and Transforming Growth Factor
1. Cancer Research (49): 29142920.
[19] Gschwind, Andreas; Fischer, Oliver M.; Ullrich, Axel
(May 2004). Timeline: The discovery of receptor tyrosine kinases: targets for cancer therapy. Nature Reviews
Cancer 4 (5): 361370. doi:10.1038/nrc1360. PMID
15122207.
[20] Summy, Justin M.; Gallick, GE (1 January 2003).
Src family kinases in tumor progression and metastasis. Cancer and Metastasis Reviews 22 (4): 337358.
doi:10.1023/A:1023772912750. PMID 12884910.
[21] Thomas, Sheila M.; Brugge, Joan S. (1 November
1997). CELLULAR FUNCTIONS REGULATED
BY SRC FAMILY KINASES. Annual Review of
Cell and Developmental Biology 13 (1): 513609.
doi:10.1146/annurev.cellbio.13.1.513. PMID 9442882.
[22] Garnett, Mathew J.; Marais, Richard (1 October 2004).
Guilty as charged: B-RAF is a human oncogene. Cancer Cell 6 (4): 313319. doi:10.1016/j.ccr.2004.09.022.
PMID 15488754.

[23] Leicht, D; Vitaly Balan; Alexander Kaplun; Vinita SinghGupta; Ludmila Kaplun; Melissa Dobson; Guri Tzivion
(August 2007). Rafkinases: Function, regulation and
role in human cancer. Biochimica et Biophysica Acta
(BBA) - Molecular Cell Research 1773 (8): 11961212.
doi:10.1016/j.bbamcr.2007.05.001.
[24] Bos, JL (Sep 1, 1989). ras oncogenes in human cancer: a review. Cancer Research 49 (17): 46829. PMID
2547513.
[25] Hilgenfeld, Rolf (1 December 1995). Regulatory GTPases. Current Opinion in Structural Biology 5 (6):
810817. doi:10.1016/0959-440X(95)80015-8. PMID
8749370.
[26] Felsher, Dean W.; Bishop, J.Michael (August 1999).
Reversible Tumorigenesis by MYC in Hematopoietic Lineages.
Molecular Cell 4 (2): 199207.
doi:10.1016/S1097-2765(00)80367-6. PMID 10488335.

External links
Drosophila Oncogenes and Tumor Suppressors The Interactive Fly

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