![Oncogenes illustration](https://upload.wikimedia.org/wikipedia/commons/d/de/Oncogenes_illustration.jpg)
An oncogene is a
gene
In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a ba ...
that has the potential to cause
cancer
Cancer is a group of diseases involving abnormal cell growth with the potential to invade or spread to other parts of the body. These contrast with benign tumors, which do not spread. Possible signs and symptoms include a lump, abnormal b ...
.
In
tumor
A neoplasm () is a type of abnormal and excessive growth of tissue. The process that occurs to form or produce a neoplasm is called neoplasia. The growth of a neoplasm is uncoordinated with that of the normal surrounding tissue, and persists ...
cells, these genes are often
mutated
In biology, a mutation is an alteration in the nucleic acid sequence of the genome of an organism, virus, or extrachromosomal DNA. Viral genomes contain either DNA or RNA. Mutations result from errors during DNA or viral replication, mitos ...
, or
expressed at high levels.
[Kimball's Biology Pages.](_blank)
"Oncogenes" Free full text
Most normal cells will undergo a programmed form of rapid cell death (
apoptosis
Apoptosis (from grc, ἀπόπτωσις, apóptōsis, 'falling off') is a form of programmed cell death that occurs in multicellular organisms. Biochemical events lead to characteristic cell changes (morphology) and death. These changes incl ...
) when critical functions are altered and malfunctioning. Activated oncogenes can cause those cells designated for apoptosis to survive and proliferate instead. Most oncogenes began as proto-oncogenes: normal genes involved in cell growth and proliferation or inhibition of apoptosis. If, through mutation, normal genes promoting cellular growth are up-regulated (gain-of-function mutation), they will predispose the cell to cancer; thus, they are termed "oncogenes". Usually multiple oncogenes, along with mutated apoptotic or tumor suppressor genes will all act in concert to cause cancer. Since the 1970s, dozens of oncogenes have been identified in human cancer. Many cancer drugs target the
protein
Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, respo ...
s encoded by oncogenes.
History
The theory of oncogenes was foreshadowed by the German biologist
Theodor Boveri
Theodor Heinrich Boveri (12 October 1862 – 15 October 1915) was a German zoologist, comparative anatomist and co-founder of modern cytology. He was notable for the first hypothesis regarding cellular processes that cause cancer, and for descr ...
in his 1914 book ''Zur Frage der Entstehung Maligner Tumoren'' (Concerning the Origin of Malignant Tumors) in which he predicted the existence of oncogenes ''(Teilungsfoerdernde Chromosomen)'' that become amplified ''(im permanenten Übergewicht)'' during tumor development.
Later on, the term "oncogene" was rediscovered in 1969 by
National Cancer Institute
The National Cancer Institute (NCI) coordinates the United States National Cancer Program and is part of the National Institutes of Health (NIH), which is one of eleven agencies that are part of the U.S. Department of Health and Human Services. ...
scientists George Todaro and
Robert Huebner
Robert Joseph Huebner (February 23, 1914 – August 26, 1998), was an American physician and virologist whose research into viruses, their causes and treatment that led to his breakthrough insights into the connections between viruses and ca ...
.
The first confirmed oncogene was discovered in 1970 and was termed
SRC (pronounced "sarc" as it is short for sarcoma). SRC was first discovered as an oncogene in a chicken
retrovirus. Experiments performed by Dr. G. Steve Martin of the
University of California, Berkeley
The University of California, Berkeley (UC Berkeley, Berkeley, Cal, or California) is a public land-grant research university in Berkeley, California. Established in 1868 as the University of California, it is the state's first land-grant u ...
demonstrated that SRC was indeed the gene of the virus that acted as an oncogene upon infection.
The first
nucleotide sequence
A nucleic acid sequence is a succession of bases signified by a series of a set of five different letters that indicate the order of nucleotides forming alleles within a DNA (using GACT) or RNA (GACU) molecule. By convention, sequences are usu ...
of
v-Src
v-Src is a gene found in Rous sarcoma virus (RSV) that encodes a tyrosine kinase that causes a type of cancer in chickens.
The src gene is oncogenic as it triggers uncontrolled growth in abnormal host cells. It was the first retroviral oncogen ...
was
sequenced
In genetics and biochemistry, sequencing means to determine the primary structure (sometimes incorrectly called the primary sequence) of an unbranched biopolymer. Sequencing results in a symbolic linear depiction known as a sequence which suc ...
in 1980 by A.P. Czernilofsky et al.
In 1976, Drs. ,
J. Michael Bishop
John Michael Bishop (born February 22, 1936) is an American immunologist and microbiologist who shared the 1989 Nobel Prize in Physiology or Medicine with Harold E. Varmus and was co-winner of 1984 Alfred P. Sloan Prize. He serves as an activ ...
and
Harold E. Varmus
Harold Eliot Varmus (born December 18, 1939) is an American Nobel Prize-winning scientist. He is currently the Lewis Thomas University Professor of Medicine at Weill Cornell Medicine and a senior associate at the New York Genome Center.
He was ...
of the
University of California, San Francisco
The University of California, San Francisco (UCSF) is a public land-grant research university in San Francisco, California. It is part of the University of California system and is dedicated entirely to health science and life science. It con ...
demonstrated that oncogenes were activated proto-oncogenes as is found in many organisms, including humans. Bishop and Varmus were awarded the
Nobel Prize in Physiology or Medicine
The Nobel Prize in Physiology or Medicine is awarded yearly by the Nobel Assembly at the Karolinska Institute for outstanding discoveries in physiology or medicine. The Nobel Prize is not a single prize, but five separate prizes that, accord ...
in 1989 for their discovery of the cellular origin of retroviral oncogenes.
Dr.
Robert Weinberg is credited with discovering the first identified human oncogene in a human
bladder cancer
Bladder cancer is any of several types of cancer arising from the tissues of the urinary bladder. Symptoms include blood in the urine, pain with urination, and low back pain. It is caused when epithelial cells that line the bladder become mali ...
cell line. The molecular nature of the mutation leading to oncogenesis was subsequently isolated and characterized by the Spanish biochemist
Mariano Barbacid
Mariano Barbacid Montalbán (born 4 October 1949 in Madrid) is a Spanish molecular biochemist who discovered the first oncogene HRAS.
Academic career
He completed his higher education in the Universidad Complutense de Madrid, where he studied ...
and published in ''
Nature
Nature, in the broadest sense, is the physics, physical world or universe. "Nature" can refer to the phenomenon, phenomena of the physical world, and also to life in general. The study of nature is a large, if not the only, part of science. ...
'' in 1982.
Dr. Barbacid spent the following months extending his research, eventually discovering that the oncogene was a mutated
allele
An allele (, ; ; modern formation from Greek ἄλλος ''állos'', "other") is a variation of the same sequence of nucleotides at the same place on a long DNA molecule, as described in leading textbooks on genetics and evolution.
::"The chro ...
of
HRAS
GTPase HRas, from "Harvey Rat sarcoma virus", also known as transforming protein p21 is an enzyme that in humans is encoded by the gene. The ''HRAS'' gene is located on the short (p) arm of chromosome 11 at position 15.5, from base pair 522,241 ...
and characterizing its activation mechanism.
The resultant protein encoded by an oncogene is termed oncoprotein.
Oncogenes 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.
Proto-oncogene
A proto-oncogene is a normal gene that could become an oncogene due to mutations or increased
expression
Expression may refer to:
Linguistics
* Expression (linguistics), a word, phrase, or sentence
* Fixed expression, a form of words with a specific meaning
* Idiom, a type of fixed expression
* Metaphorical expression, a particular word, phrase, o ...
. Proto-oncogenes code for
protein
Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, respo ...
s that help to regulate the
cell growth and
differentiation. Proto-oncogenes are often involved in
signal transduction
Signal transduction is the process by which a chemical or physical signal is transmitted through a cell as a series of molecular events, most commonly protein phosphorylation catalyzed by protein kinases, which ultimately results in a cellula ...
and execution of
mitogenic
A mitogen is a small bioactive protein or peptide that induces a cell to begin cell division, or enhances the rate of division (mitosis). Mitogenesis is the induction (triggering) of mitosis, typically via a mitogen. The mechanism of action of a ...
signals, usually through their
protein
Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, respo ...
products. Upon acquiring an activating mutation, a proto-oncogene becomes a tumor-inducing agent, an oncogene. Examples of proto-oncogenes include
RAS
Ras or RAS may refer to:
Arts and media
* RAS Records Real Authentic Sound, a reggae record label
* Rundfunk Anstalt Südtirol, a south Tyrolese public broadcasting service
* Rás 1, an Icelandic radio station
* Rás 2, an Icelandic radio stati ...
,
WNT,
MYC
''Myc'' is a family of regulator genes and proto-oncogenes that code for transcription factors. The ''Myc'' family consists of three related human genes: ''c-myc'' (MYC), ''l-myc'' ( MYCL), and ''n-myc'' (MYCN). ''c-myc'' (also sometimes refe ...
,
ERK, and
TRK. The MYC gene is implicated in
Burkitt's lymphoma, which starts when a
chromosomal translocation
In genetics, chromosome translocation is a phenomenon that results in unusual rearrangement of chromosomes. This includes balanced and unbalanced translocation, with two main types: reciprocal-, and Robertsonian translocation. Reciprocal translo ...
moves an
enhancer sequence
In genetics, an enhancer is a short (50–1500 bp) region of DNA that can be bound by protein
Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast ar ...
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
The Philadelphia chromosome or Philadelphia translocation (Ph) is a specific genetic abnormality in chromosome 22 of leukemia cancer cells (particularly chronic myeloid leukemia (CML) cells). This chromosome is defective and unusually short becaus ...
gene found on the
Philadelphia chromosome
The Philadelphia chromosome or Philadelphia translocation (Ph) is a specific genetic abnormality in chromosome 22 of leukemia cancer cells (particularly chronic myeloid leukemia (CML) cells). This chromosome is defective and unusually short becaus ...
, 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 tyrosine kinase, which is constitutively active, leading to uncontrolled cell proliferation. (More information about the Philadelphia Chromosome below)
Activation
The proto-oncogene can become an oncogene by a relatively small modification of its original function. There are three basic methods of activation:
#A
mutation
In biology, a mutation is an alteration in the nucleic acid sequence of the genome of an organism, virus, or extrachromosomal DNA. Viral genomes contain either DNA or RNA. Mutations result from errors during DNA or viral replication, mi ...
within a proto-oncogene, or within a regulatory region (for example the promoter region), can cause a change in the protein structure, causing
#* an increase in protein (
enzyme
Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrates, and the enzyme converts the substrates into different molecules known as products. A ...
) activity
#* a loss of
regulation
Regulation is the management of complex systems according to a set of rules and trends. In systems theory, these types of rules exist in various fields of biology and society, but the term has slightly different meanings according to context. For ...
# An increase in the amount of a certain protein (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
#*
gene duplication (one type of
chromosome abnormality
A chromosomal abnormality, chromosomal anomaly, chromosomal aberration, chromosomal mutation, or chromosomal disorder, is a missing, extra, or irregular portion of Chromosome, chromosomal DNA. These can occur in the form of numerical abnormalities ...
), resulting in an increased amount of protein in the cell
# A
chromosomal translocation
In genetics, chromosome translocation is a phenomenon that results in unusual rearrangement of chromosomes. This includes balanced and unbalanced translocation, with two main types: reciprocal-, and Robertsonian translocation. Reciprocal translo ...
(another type of
chromosome abnormality
A chromosomal abnormality, chromosomal anomaly, chromosomal aberration, chromosomal mutation, or chromosomal disorder, is a missing, extra, or irregular portion of Chromosome, chromosomal DNA. These can occur in the form of numerical abnormalities ...
)
#*There are 2 different types of chromosomal translocations that can occur:
##translocation events which relocate a proto-oncogene to a new chromosomal site that leads to higher expression
##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 multicellular organisms, stem cells are undifferentiated or partially differentiated cells that can differentiate into various types of cells and proliferate indefinitely to produce more of the same stem cell. They are the earliest type o ...
in the
bone marrow leads to adult
leukemia
Leukemia ( also spelled leukaemia and pronounced ) is a group of blood cancers that usually begin in the bone marrow and result in high numbers of abnormal blood cells. These blood cells are not fully developed and are called ''blasts'' or ' ...
##*Philadelphia Chromosome is an example of this type of translocation event. This chromosome was discovered in 1960 by
Peter Nowell
Peter Carey Nowell (February 8, 1928 – December 26, 2016) was a cancer researcher and co-discoverer of the Philadelphia chromosome. At the time of his death, he was the Gaylord P. and Mary Louise Harnwell Emeritus Professor of Pathology and Labo ...
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
Tyrosine-protein kinase ABL1 also known as ABL1 is a protein that, in humans, is encoded by the ''ABL1'' gene (previous symbol ''ABL'') located on chromosome 9. c-Abl is sometimes used to refer to the version of the gene found within the mammalian ...
" 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 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.
The expression of oncogenes can be regulated by
microRNA
MicroRNA (miRNA) are small, single-stranded, non-coding RNA molecules containing 21 to 23 nucleotides. Found in plants, animals and some viruses, miRNAs are involved in RNA silencing and post-transcriptional regulation of gene expression. mi ...
s (miRNAs), small
RNA
Ribonucleic acid (RNA) is a polymeric molecule essential in various biological roles in coding, decoding, regulation and expression of genes. RNA and deoxyribonucleic acid ( DNA) are nucleic acids. Along with lipids, proteins, and carbohydra ...
s 21-25 nucleotides in length that control gene expression by
downregulating them.
Mutations in such
microRNAs
MicroRNA (miRNA) are small, single-stranded, non-coding RNA molecules containing 21 to 23 nucleotides. Found in plants, animals and some viruses, miRNAs are involved in RNA silencing and post-transcriptional regulation of gene expression. miR ...
(known as
oncomir An oncomir (also oncomiR) is a microRNA (miRNA) that is associated with cancer. MicroRNAs are short RNA molecules about 22 nucleotides in length. Essentially, miRNAs specifically target certain messenger RNAs (mRNAs) to prevent them from coding fo ...
s) can lead to activation of oncogenes.
Antisense
In molecular biology and genetics, the sense of a nucleic acid molecule, particularly of a strand of DNA or RNA, refers to the nature of the roles of the strand and its complement in specifying a sequence of amino acids. Depending on the context ...
messenger RNAs could theoretically be used to block the effects of oncogenes.
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:
Additional oncogenetic regulator properties include:
::*Growth factors are usually
secreted 440px
Secretion is the movement of material from one point to another, such as a secreted chemical substance from a cell or gland. In contrast, excretion is the removal of certain substances or waste products from a cell or organism. The classical ...
by either specialized or non-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, possibly leading to tumor formation. It may also cause production of growth hormones in other parts of the body.
::*
Receptor tyrosine kinase
Receptor tyrosine kinases (RTKs) are the high- affinity cell surface receptors for many polypeptide growth factors, cytokines, and hormones. Of the 90 unique tyrosine kinase genes identified in the human genome, 58 encode receptor tyrosine kin ...
s add phosphate groups to other proteins in order to turn them on or off. Receptor kinases add phosphate groups to receptor proteins at the surface of the cell (which receives protein signals from outside the cell and transmits 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.
::*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 as a binary switch (on/off) 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
*
Anticancer gene When overexpressed ectopically, anticancer genes are those that preferentially kill cancer cells while sparing normal, healthy cells. Apoptosis, necrosis, or apoptosis following a mitotic catastrophe, and autophagy are only a few of the processes th ...
*
Oncogenomics
Oncogenomics is a sub-field of genomics that characterizes cancer-associated genes. It focuses on genomic, epigenomic and transcript alterations in cancer.
Cancer is a genetic disease caused by accumulation of DNA mutations and epigenetic alte ...
*
Tumor suppressor gene
A tumor suppressor gene (TSG), or anti-oncogene, is a gene that regulates a cell during cell division and replication. If the cell grows uncontrollably, it will result in cancer. When a tumor suppressor gene is mutated, it results in a loss or red ...
*
Oncovirus
An oncovirus or oncogenic virus is a virus that can cause cancer. This term originated from studies of acutely transforming retroviruses in the 1950–60s, when the term "oncornaviruses" was used to denote their RNA virus origin. With the lette ...
*
Genetic predisposition
*
Quantitative trait locus
A quantitative trait locus (QTL) is a locus (section of DNA) that correlates with variation of a quantitative trait in the phenotype of a population of organisms. QTLs are mapped by identifying which molecular markers (such as SNPs or AFLPs) c ...
*
Genetic susceptibility
Public health genomics is the use of genomics information to benefit public health. This is visualized as more effective preventive care and disease treatments with better Specificity (statistics), specificity, tailored to the genetic makeup of ea ...
*
Oncometabolism Oncometabolism is the field of study that focuses on the metabolic changes that occur in cells that make up the tumor microenvironment (TME) and accompany oncogenesis and tumor progression toward a neoplastic state.
Cells with increased growth an ...
References
External links
''Drosophila'' Oncogenes and Tumor Suppressors - The Interactive Fly
{{Authority control
Carcinogenesis