Anoncogene is agene that has the potential to causecancer.[1] Intumorcells, these genes are oftenmutated, orexpressed at high levels.[2]
Most normal cells undergo a preprogrammed rapid cell death (apoptosis) if critical functions are altered and then malfunction. 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, through mutation, normal genes promoting cellular growth are up-regulated (gain-of-function mutation), they predispose the cell to cancer and are termedoncogenes. Usually, multiple oncogenes, along with mutated apoptotic ortumor suppressor genes, act in concert to cause cancer. Since the 1970s, dozens of oncogenes have been identified in human cancer. Many cancer drugs target theproteins encoded by oncogenes.[2][4][5][6] Oncogenes are a physically and functionally diverse set of genes, and as a result, their protein products havepleiotropic effects on a variety of intricate regulatory cascades within the cell.
Genes known as proto-oncogenes are those that normally encourage cell growth and division in order to generate new cells or sustain the viability of pre-existing cells. When overexpressed, proto-oncogenes can be inadvertently activated (turned on), which changes them to oncogenes.[7]
There are numerous ways to activate (turn on) oncogenes in cells:
Gene changes or mutations: A person's genetic "coding" may differ in a way that causes an oncogene to always be activated. These types of gene changes can develop spontaneously throughout the course of a person's life or they might be inherited from a parent when atranscription error occurs during cell division.[8]
Cells can frequently switch genes on or off via epigenetic mechanisms rather than actual genetic alterations. Alternately, different chemical compounds that can be linked to genetic material (DNA or RNA) may have an impact on which genes are active. An oncogene may sporadically become activated due to these epigenetic modifications. Visit Gene Alterations and Cancer to learn more about epigenetic alterations.
Chromosomal rearrangement: Every living creature has chromosomes, which are substantial strands ofDNA that contain the genes for a cell. A chromosome's DNA sequence may alter each time a cell divides. This could cause a gene to be located near to a proto-oncogene that acts as an "on" switch, keeping it active even when it shouldn't. The cell can develop irregularly with the aid of this new oncogene.[9]
Gene duplication: If one cell has more copies of a gene than another, that cell may produce too much of a certain protein.
The first human oncogene (HRAS), a crucial finding in the field of cancer research, was discovered more than 40 years ago, and since then, the number of novel pathogenic oncogenes has increased steadily. The discovery of specific small-molecule inhibitors that specifically target the different oncogenic proteins and a comprehensive mechanistic analysis of the ways in which oncogenes dysregulate physiological signaling to cause different cancer types and developmental syndromes are potential future advances in the field of cancer research. Investigating the quickly expanding field of oncogene molecular research, the goal of this special issue was to generate practical translational indicators that could be able to meet clinical needs.[10]
Genes that are considered crucial for cancer can be divided into two categories based on whether the harmful mutations in them result in function loss or gain. Gain-of-function mutations of proto-oncogenes drive cells to proliferate when they shouldn't, while loss-of-function mutations of tumor suppressor genes free cells from inhibitions that typically serve to control their numbers. The ability of the mutant genes, known as oncogenes, to steer a specific line of test cells toward malignant proliferation can occasionally be used to identify these later mutations, which have a dominating effect.
Many of them were initially found to induce cancer in animals when they are introduced through viral vector infection, which carries genetic information from a prior host cell. Another method for identifying oncogenes is to look for genes that are activated by mutations in human cancer cells or by chromosomal translocations that may indicate the presence of a gene that is crucial for cancer.[11]
Cancer patients are generally categorized according to clinical parameters in order to tailor theircancer therapy. For example, the separation of patients withacute leukemia into those withlymphocytic leukemia and those withmyelocytic leukemia is important, because the optimal treatment for each form is different. Even in a particular disease, the identification of patients with good and poorprognostic potential is helpful, since more aggressive therapy may be needed to achieve a cure in the poor prognostic group. Oncogenes areprognostic markers in certain human cancers.N-myc amplification is an independent determinant in predicting a poor outcome in childhoodneuroblastoma. Those children with amplification of N-myc, regardless of stage, will have shortened survival. Thus, therapeutic efforts are concentrated on intensifying treatment in this poor prognostic group.[12]
The theory of oncogenes was foreshadowed by the German biologistTheodor Boveri in his 1914 bookZur 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.[13]
Later on, the term "oncogene" was rediscovered in 1969 byNational Cancer Institute scientists George Todaro andRobert Huebner.[14]
The first confirmed oncogene was discovered in 1970 and was termedSRC (pronounced "sarc" as it is short for sarcoma). SRC was first discovered as an oncogene in a chickenretrovirus. Experiments performed by Dr. G. Steve Martin of theUniversity of California, Berkeley demonstrated that SRC was indeed the gene of the virus that acted as an oncogene upon infection.[15] The firstnucleotide sequence ofv-Src wassequenced in 1980 by A.P. Czernilofsky et al.[16]
In 1976, Drs.Dominique Stéhelin [fr],J. Michael Bishop andHarold E. Varmus of theUniversity of California, San Francisco demonstrated that oncogenes were activated proto-oncogenes as is found in many organisms, including humans. Bishop and Varmus were awarded theNobel Prize in Physiology or Medicine in 1989 for their discovery of the cellular origin of retroviral oncogenes.[17]
Dr.Robert Weinberg is credited with discovering the first identified human oncogene in a humanbladder cancer cell line.[18][19] The molecular nature of the mutation leading to oncogenesis was subsequently isolated and characterized by the Spanish biochemistMariano Barbacid and published inNature in 1982.[20] Dr. Barbacid spent the following months extending his research, eventually discovering that the oncogene was a mutatedallele ofHRAS and characterizing its activation mechanism.
The resultant protein encoded by an oncogene is termedoncoprotein.[21] 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.
Aproto-oncogene is a normal gene that could become an oncogene due to mutations or increasedexpression. Proto-oncogenes code forproteins that help to regulate thecell growth anddifferentiation. Proto-oncogenes are often involved insignal transduction and execution ofmitogenic signals, usually through theirprotein products. Upon acquiring an activating mutation, a proto-oncogene becomes a tumor-inducing agent, an oncogene.[22] Examples of proto-oncogenes includeRAS,WNT,MYC,ERK, andTRK. The MYC gene is implicated inBurkitt's lymphoma, which starts when achromosomal translocation moves anenhancer 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 theBcr-Abl gene found on thePhiladelphia 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)
The proto-oncogene can become an oncogene by a relatively small modification of its original function. There are three basic methods of activation:
The expression of oncogenes can be regulated bymicroRNAs (miRNAs), smallRNAs 21-25 nucleotides in length that control gene expression bydownregulating them.[24] Mutations in suchmicroRNAs (known asoncomirs) can lead to activation of oncogenes.[25]Antisense messenger RNAs could theoretically be used to block the effects of oncogenes.
There are several systems for classifying oncogenes,[26] 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 | Cancers | Gene functions |
|---|---|---|---|
| Growth factors, or mitogens | c-Sis | glioblastomas,fibrosarcomas,osteosarcomas,breast carcinomas, andmelanomas[27] | induces cell proliferation. |
| Receptor tyrosine kinases | epidermal growth factor receptor (EGFR),platelet-derived growth factor receptor (PDGFR), andvascular endothelial growth factor receptor (VEGFR),HER2/neu | Breast cancer, gastrointestinal stromal tumours, non-small-cell lung cancer and pancreatic cancer[28] | transduce signals for cell growth and differentiation. |
| Cytoplasmictyrosine kinases | Src-family,Syk-ZAP-70 family, andBTK 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[29] | mediate the responses to, and the activation receptors of cell proliferation, migration, differentiation, and survival[30] |
| CytoplasmicSerine/threonine kinases and their regulatory subunits | Raf kinase, andcyclin-dependent kinases (throughoverexpression). | malignant melanoma, papillary thyroid cancer, colorectal cancer, and ovarian cancer[31] | involved in organism development, cell cycle regulation, cell proliferation, differentiation, cells survival, and apoptosis[32] |
| RegulatoryGTPases | Ras protein | adenocarcinomas of the pancreas and colon, thyroid tumors, and myeloid leukemia[33] | involved in signalling a major pathway leading to cell proliferation.[34] |
| Transcription factors | myc gene | malignant T-cell lymphomas and acute myeloid leukemias, breast cancer, pancreatic cancer, retinoblastoma, and small cell lung cancer[35] | regulate transcription of genes that induce cell proliferation. |
| Transcriptional coactivators | YAP,WWTR1 genes | glioma, melanoma, lung cancer, breast cancers, and more[36] | interact with transcription factor partners to regulate transcription of genes that induce cell proliferation. |
Additional oncogenetic regulator properties include:
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