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 b ...

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, or expressed at high levels.Kimball's Biology Pages.
"Oncogenes" Free full text Most normal cells will undergo a programmed form of rapid cell death ( apoptosis) 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, res ...

s encoded by oncogenes.

History

The theory of oncogenes was foreshadowed by the German biologist Theodor Boveri 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 scientists George Todaro and Robert Huebner. 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 of v-Src 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 ma ...

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 physical world or universe. "Nature" can refer to the 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. Although humans are ...

'' 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 ...

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

s that help to regulate the cell growth and differentiation. Proto-oncogenes are often involved in signal transduction 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

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 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 replication, DNA or viral repl ...

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 ...

) 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. Fo ...

# 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

(another type of

) #*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 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 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 RNAs 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 oncomirs) 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.

References

External links