Oncogene

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Illustration of how a normal cell is converted to a cancer cell, when an oncogene becomes activated Oncogenes illustration.jpg
Illustration of how a normal cell is converted to a cancer cell, when an oncogene becomes activated

An oncogene is a gene that has the potential to cause cancer. [1] In tumor cells, they are often mutated or expressed at high levels. [2]

Gene basic physical and functional unit of heredity

In biology, a gene is a sequence of nucleotides in DNA or RNA that codes for a molecule that has a function. During gene expression, the DNA is first copied into RNA. The RNA can be directly functional or be the intermediate template for a protein that performs a function. The transmission of genes to an organism's offspring is the basis of the inheritance of phenotypic trait. These genes make up different DNA sequences called genotypes. Genotypes along with environmental and developmental factors determine what the phenotypes will be. Most biological traits are under the influence of polygenes as well as gene–environment interactions. Some genetic traits are instantly visible, such as eye color or number of limbs, and some are not, such as blood type, risk for specific diseases, or the thousands of basic biochemical processes that constitute life.

Cancer disease of uncontrolled, unregulated and abnormal cell growth

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 bleeding, prolonged cough, unexplained weight loss and a change in bowel movements. While these symptoms may indicate cancer, they can also have other causes. Over 100 types of cancers affect humans.

Gene expression The process in which a genes sequence is converted into a mature gene product or products (proteins or RNA). This includes the production of an RNA transcript as well as any processing to produce a mature RNA product or an mRNA or circRNA (for prote

Gene expression is the process by which information from a gene is used in the synthesis of a functional gene product. These products are often proteins, but in non-protein coding genes such as transfer RNA (tRNA) or small nuclear RNA (snRNA) genes, the product is a functional RNA.

Contents

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. [3] Most oncogenes began as proto-oncogenes, normal genes involved in cell growth and proliferation or inhibition of apoptosis. If normal genes promoting cellular growth, through mutation, are up-regulated, (gain of function mutation) they will predispose the cell to cancer and are thus 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 proteins encoded by oncogenes. [2] [4] [5] [6]

Apoptosis programmed cell death process

Apoptosis is a form of programmed cell death that occurs in multicellular organisms. Biochemical events lead to characteristic cell changes (morphology) and death. These changes include blebbing, cell shrinkage, nuclear fragmentation, chromatin condensation, chromosomal DNA fragmentation, and global mRNA decay. The average adult human loses between 50 and 70 billion cells each day due to apoptosis. For an average human child between the ages of 8 to 14 year old approximately 20 to 30 billion cells die per day.

Protein biological molecule consisting of chains of amino acid residues

Proteins are large biomolecules, or macromolecules, consisting of one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, responding to stimuli, providing structure to cells and organisms, and transporting molecules from one location to another. Proteins differ from one another primarily in their sequence of amino acids, which is dictated by the nucleotide sequence of their genes, and which usually results in protein folding into a specific three-dimensional structure that determines its activity.

History

The theory of oncogenes was foreshadowed by the German biologist Theodor Boveri in his 1914 book Zur Frage der Entstehung Maligner Tumoren ('The Origin of Malignant Tumours'), Gustav Fisher, Jena, 1914. Oncogenes (Teilungsfoerdernde Chromosomen) that become amplified (im permanenten Übergewicht) during tumour development.

Later on the term "oncogene" was rediscovered in 1969 by National Cancer Institute scientists George Todaro and Robert Heubner. [7]

National Cancer Institute US research institute, part of National Institutes of Health

The National Cancer Institute (NCI) 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. The NCI coordinates the United States National Cancer Program and conducts and supports research, training, health information dissemination, and other activities related to the causes, prevention, diagnosis, and treatment of cancer; the supportive care of cancer patients and their families; and cancer survivorship.

The first confirmed oncogene was discovered in 1970 and was termed sarcom. Sarcoma 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 sarcoma was indeed the oncogene of the virus. [8] The first nucleotide sequence of v-sarcoma was sequenced in 1980 by A.P. Czernilofsky et al. [9]

Retrovirus family of viruses

A retrovirus is a type of RNA virus that inserts a copy of its genome into the DNA of a host cell that it invades, thus changing the genome of that cell. Such viruses are specifically classified as single-stranded positive-sense RNA viruses.

University of California, Berkeley Public university in California, USA

The University of California, Berkeley is a public research university in Berkeley, California. It was founded in 1868 and serves as the flagship institution of the ten research universities affiliated with the University of California system. Berkeley has since grown to instruct over 40,000 students in approximately 350 undergraduate and graduate degree programs covering numerous disciplines.

Nucleic acid sequence A succession of nucleotides in a nucleic acid

A nucleic acid sequence is a succession of letters that indicate the order of nucleotides forming alleles within a DNA or RNA (GACU) molecule. By convention, sequences are usually presented from the 5' end to the 3' end. For DNA, the sense strand is used. Because nucleic acids are normally linear (unbranched) polymers, specifying the sequence is equivalent to defining the covalent structure of the entire molecule. For this reason, the nucleic acid sequence is also termed the primary structure.

In 1976 Drs. Dominique Stehelin, J. Michael Bishop and Harold E. Varmus of the University of California, San Francisco demonstrated that oncogenes were activated proto-oncogenes, found in many organisms including humans. Bishop and Varmus were awarded the Nobel Prize in Physiology or Medicine in 1989 for their discovery of the cellular origin of retroviral oncogenes. [10]

J. Michael Bishop American immunologist and microbiologist

John Michael Bishop 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 active faculty member at the University of California, San Francisco (UCSF), where he also served as Chancellor from 1998 to 2009.

Harold E. Varmus American scientist

Harold Eliot Varmus is an American Nobel Prize-winning scientist who was director of the National Institutes of Health from 1993 to 1999 and the 14th Director of the National Cancer Institute from 2010 to 2015, a post to which he was appointed by President Barack Obama. He was a co-recipient of the 1989 Nobel Prize in Physiology or Medicine for discovery of the cellular origin of retroviral oncogenes. He is currently the Lewis Thomas University Professor of Medicine at Weill Cornell Medicine and a Senior Associate at the New York Genome Center.

University of California, San Francisco university

The University of California, San Francisco (UCSF) is a public research university in San Francisco, California. It is part of the University of California system and it is dedicated entirely to health science. It is a major center of medical and biological research and teaching.

The resultant protein encoded by an oncogene is termed oncoprotein. [11] 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. The Spanish biochemist Mariano Barbacid isolated the first oncogene. His discovery was published in the prestigious journal Nature in 1982 in an article titled "A point mutation is responsible for the acquisition of transforming properties by the T24 human bladder-carcinoma oncogene". [12] He spent the following months extending his research, eventually discovering that such oncogene was the mutation of an allele of the Ras subfamily, as well as its activation mechanism.

Mariano Barbacid is a Spanish molecular biochemist who discovered the first oncogene. His discovery was published in the prestigious journal Nature in 1982 in an article titled "A point mutation is responsible for the acquisition of transforming properties by the T24 human bladder-carcinoma oncogene". He spent the following months extending his research, eventually discovering that such oncogene was the mutation of an allele of the Ras subfamily, as well as its activation mechanism.

An allele is a variant form of a given gene. Sometimes, the presence of different alleles of the same gene can result in different observable phenotypic traits, such as different pigmentation. A notable example of this trait of color variation is Gregor Mendel's discovery that the white and purple flower colors in pea plants were the result of "pure line" traits which could be used as a control for future experiments. However, most genetic variations result in little or no observable variation.

Ras subfamily chemical compound

Ras is a family of related proteins which is expressed in all animal cell lineages and organs. All Ras protein family members belong to a class of protein called small GTPase, and are involved in transmitting signals within cells. Ras is the prototypical member of the Ras superfamily of proteins, which are all related in 3D structure and regulate diverse cell behaviours.

Proto-oncogene

A proto-oncogene is a normal gene that could become an oncogene due to mutations or increased expression. Proto-oncogenes code for proteins that help to regulate the cell growth and differentiation. Proto-oncogenes are often involved in signal transduction and execution of mitogenic signals, usually through their protein products. Upon acquiring an activating mutation, a proto-oncogene becomes a tumor-inducing agent, an oncogene. [13] Examples of proto-oncogenes include RAS, WNT, MYC, ERK, and TRK. The MYC gene is implicated in Burkitt's 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. Bcr-Abl codes for a tyrosine kinase, which is constitutively active, leading to uncontrolled cell proliferation. (More information about the Philadelphia Chromosome below)

Activation

From proto-oncogene to oncogene Ch1-oncogene.svg
From proto-oncogene to oncogene

The proto-oncogene can become an oncogene by a relatively small modification 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
  2. 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), resulting in an increased amount of protein in the cell
  3. A chromosomal translocation (another type of chromosome abnormality)
    • There are 2 different types of chromosomal translocations that can occur:
    1. translocation events which relocate a proto-oncogene to a new chromosomal site that leads to higher expression
    2. 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 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. [14]

The expression of oncogenes can be regulated by microRNAs (miRNAs), small RNAs 21-25 nucleotides in length that control gene expression by downregulating them. [15] Mutations in such microRNAs (known as oncomirs) can lead to activation of oncogenes. [16] Antisense messenger RNAs could theoretically be used to block the effects of oncogenes.

Classification

There are several systems for classifying oncogenes, [17] 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:

CategoryExamplesCancersGene functions
Growth factors, or mitogens c-Sis glioblastomas, fibrosarcomas, osteosarcomas, breast carcinomas, and melanomas [18] induces cell proliferation.
Receptor tyrosine kinases epidermal growth factor receptor (EGFR), platelet-derived growth factor receptor (PDGFR), and vascular endothelial growth factor receptor (VEGFR), HER2/neu Breast cancer, gastrointestinal stromal tumours, non-small-cell lung cancer and pancreatic cancer [19] transduce signals for cell growth and differentiation.
Cytoplasmic tyrosine kinases Src-family, Syk-ZAP-70 family, and BTK family of tyrosine kinases, the Abl gene in CML - Philadelphia chromosome colorectal and breast cancers, melanomas, ovarian cancers, gastric cancers, head and neck cancers, pancreatic cancer, lung cancer, brain cancers, and blood cancers [20] mediate the responses to, and the activation receptors of cell proliferation, migration, differentiation, and survival [21]
Cytoplasmic Serine/threonine kinases and their regulatory subunits Raf kinase, and cyclin-dependent kinases (through overexpression).malignant melanoma, papillary thyroid cancer, colorectal cancer, and ovarian cancer [22] Involved in organism development, cell cycle regulation, cell proliferation, differentiation, cells survival, and apoptosis [23]
Regulatory GTPases Ras protein adenocarcinomas of the pancreas and colon, thyroid tumors, and myeloid leukemia [24] involved in signalling a major pathway leading to cell proliferation. [25]
Transcription factors myc genemalignant T-cell lymphomas and acute myleoid leukemias, breast cancer, pancreatic cancer, retinoblastoma, and small cell lung cancer [26] -They regulate transcription of genes that induce cell proliferation.

Additional oncogenetic regulator properties include:

  • Growth factors are usually secreted 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 kinases 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 like 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. [27]

See also

Related Research Articles

Tyrosine kinase enzyme that can add a phosphate group from ATP to a cellular protein

A tyrosine kinase is an enzyme that can transfer a phosphate group from ATP to a protein in a cell. It functions as an "on" or "off" switch in many cellular functions. Tyrosine kinases are a subclass of protein kinase.

Philadelphia chromosome Philadelphia chromosome or Philadelphia translocation is a specific chromosomal abnormality that is associated with chronic myelogenous leukemia (CML).

The Philadelphia chromosome or Philadelphia translocation (Ph) is a specific genetic abnormality in chromosome 22 of leukemia cancer cells. This chromosome is defective and unusually short because of reciprocal translocation, t(9;22)(q34;q11), of genetic material between chromosome 9 and chromosome 22, and contains a fusion gene called BCR-ABL1. This gene is the ABL1 gene of chromosome 9 juxtaposed onto the breakpoint cluster region BCR gene of chromosome 22, coding for a hybrid protein: a tyrosine kinase signalling protein that is "always on", causing the cell to divide uncontrollably by interrupting the stability of the genome and impairing various signaling pathways governing the cell cycle.

Carcinogenesis, also called oncogenesis or tumorigenesis, is the formation of a cancer, whereby normal cells are transformed into cancer cells. The process is characterized by changes at the cellular, genetic, and epigenetic levels and abnormal cell division. Cell division is a physiological process that occurs in almost all tissues and under a variety of circumstances. Normally the balance between proliferation and programmed cell death, in the form of apoptosis, is maintained to ensure the integrity of tissues and organs. According to the prevailing accepted theory of carcinogenesis, the somatic mutation theory, mutations in DNA and epimutations that lead to cancer disrupt these orderly processes by disrupting the programming regulating the processes, upsetting the normal balance between proliferation and cell death. This results in uncontrolled cell division and the evolution of those cells by natural selection in the body. Only certain mutations lead to cancer whereas the majority of mutations do not.

ABL (gene) protein-coding gene in the species Homo sapiens

Abelson murine leukemia viral oncogene homolog 1 also known as ABL1 is a protein that, in humans, is encoded by the ABL1 gene located on chromosome 9. c-Abl is sometimes used to refer to the version of the gene found within the mammalian genome, while v-Abl refers to the viral gene.

The MAPK/ERK pathway is a chain of proteins in the cell that communicates a signal from a receptor on the surface of the cell to the DNA in the nucleus of the cell.

Myc protein-coding gene in the species Homo sapiens

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, l-myc, and n-myc. c-myc was the first gene to be discovered in this family, due to homology with the viral gene v-myc.

CD117 protein-coding gene in the species Homo sapiens

Mast/stem cell growth factor receptor (SCFR), also known as proto-oncogene c-Kit or tyrosine-protein kinase Kit or CD117, is a receptor tyrosine kinase protein that in humans is encoded by the KIT gene. Multiple transcript variants encoding different isoforms have been found for this gene. KIT was first described by the German biochemist Axel Ullrich in 1987 as the cellular homolog of the feline sarcoma viral oncogene v-kit.

BCR (gene) protein-coding gene in the species Homo sapiens

The breakpoint cluster region protein (BCR) also known as renal carcinoma antigen NY-REN-26 is a protein that in humans is encoded by the BCR gene. BCR is one of the two genes in the BCR-ABL complex, which is associated with the Philadelphia chromosome. Two transcript variants encoding different isoforms have been found for this gene.

v-Src is a gene found in Rous sarcoma virus that encodes a tyrosine kinase that causes a type of cancer in chickens.

STAT5

Signal transducer and activator of transcription 5 (STAT5) refers to two highly related proteins, STAT5A and STAT5B, which are part of the seven-membered STAT family of proteins. Though STAT5A and STAT5B are encoded by separate genes, the proteins are 90% identical at the amino acid level. STAT5 proteins are involved in cytosolic signalling and in mediating the expression of specific genes. Aberrant STAT5 activity has been shown to be closely connected to a wide range of human cancers, and silencing this aberrant activity is an area of active research in medicinal chemistry.

Acute myeloblastic leukemia with maturation

Acute myeloblastic leukemia with maturation (M2) is a subtype of acute myeloid leukemia (AML).

Fibroblast growth factor receptor 1 protein-coding gene in the species Homo sapiens

Fibroblast growth factor receptor 1 (FGFR1), also known as basic fibroblast growth factor receptor 1, fms-related tyrosine kinase-2 / Pfeiffer syndrome, and CD331, is a receptor tyrosine kinase whose ligands are specific members of the fibroblast growth factor family. FGFR1 has been shown to be associated with Pfeiffer syndrome.

ETV6 protein-coding gene in the species Homo sapiens

ETV6 protein is a transcription factor that in humans is encoded by the ETV6 gene. The ETV6 protein regulates the development and growth of diverse cell types, particularly those of hematological tissues. However, its gene, ETV6 frequently suffers various mutations that lead to an array of potentially lethal cancers, i.e., ETV6 is a clinically significant proto-oncogene in that it can fuse with other genes to drive the development and/or progression of certain cancers. However, ETV6 is also an anti-oncogene or tumor suppressor gene in that mutations in it that encode for a truncated and therefore inactive protein are also associated with certain types of cancers.

Proto-oncogene tyrosine-protein kinase Src protein-coding gene in the species Homo sapiens

Proto-oncogene tyrosine-protein kinase Src, also known as proto-oncogene c-Src or simply c-Src , is a non-receptor tyrosine kinase protein that in humans is encoded by the SRC gene. This protein phosphorylates specific tyrosine residues in other proteins.

Feline sarcoma oncogene protein-coding gene in the species Homo sapiens

Tyrosine-protein kinase Fes/Fps also known as proto-oncogene c-Fes/Fps is an enzyme that in humans is encoded by the FES gene. FES was originally cloned as a retroviral oncogene from feline (v-FES) and avian (v-FPS) sarcomas. This triggered the subsequent identification and cloning of the cellular FES (c-FES) genes in birds and mammals.

ABL2 protein-coding gene in the species Homo sapiens

Tyrosine-protein kinase ABL2 also known as Abelson-related gene (Arg) is an enzyme that in humans is encoded by the ABL2 gene.

MST1R protein-coding gene in the species Homo sapiens

Macrophage-stimulating protein receptor is a protein that in humans is encoded by the MST1R gene. MST1R is also known as RON kinase, named after the French city in which it was discovered. It is related to the c-MET receptor tyrosine kinase.

Antineoplastic resistance, often used interchangeably with chemotherapy resistance, is the resistance of neoplastic (cancerous) cells, or the ability of cancer cells to survive and grow despite anti-cancer therapies. In some cases, cancers can evolve resistance to multiple drugs, called multiple drug resistance.

Clonal hypereosinophilia, also termed primary hypereosinophilia or clonal eosinophilia, is a grouping of hematological disorders all of which are characterized by the development and growth of a pre-malignant or malignant population of eosinophils, a type of white blood cell that occupies the bone marrow, blood, and other tissues. This population consists of a clone of eosinophils, i.e. a group of genetically identical eosinophils derived from a sufficiently mutated ancestor cell.

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