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Kufe DW, Pollock RE, Weichselbaum RR, et al., editors. Holland-Frei Cancer Medicine. 6th edition. Hamilton (ON): BC Decker; 2003.
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Discoextremely and identification of oncogenes
Marco A. Pierotti, PhD, Gabriella Sozzi, PhD, and also Carlo M. Croce, MD.
The first oncogenes were uncovered via the study of retrovirsupplies, RNA tumor virprovides whose genomes are reverse-transcribed into DNA in infected animal cells.9 Throughout the course of infection, retroviral DNA is inserted right into the chromosomes of hold cells. The incorporated retroviral DNA, dubbed the provirus, replicates along with the cellular DNA of the hold.10 Transcription of the DNA provirus leads to the manufacturing of viral progeny that bud with the organize cell membrane to infect other cells. Two categories of retroviroffers are classified by their time course of tumor development in experimental pets. Acutely transforming retrovirsupplies can quickly cause tumors within days after injection. These retroviroffers deserve to also transcreate cell cultures to the neoplastic phenoform. Chronic or weakly oncogenic retrovirprovides have the right to reason tissue-specific tumors in prone strains of experimental animals after a latency duration of many kind of months. Although weakly oncogenic retrovirsupplies deserve to replicate in vitro, these virprovides carry out not transcreate cells in society.
Retroviral oncogenes are transformed versions of host cellular protooncogenes that have actually been integrated into the retroviral genome by recombicountry via hold DNA, a procedure recognized as retroviral transduction.11 This surprising discovery was made with study of the Rous sarcoma virus (RSV) (Figure 6-1). RSV is an acutely transforming retrovirus first isolated from a chicken sarcoma over 80 years earlier by Peyton Rous.12 Studies of RSV mutants in the at an early stage 1970s revealed that the transforming gene of RSV was not forced for viral replication.13–15 Molecular hybridization research studies then proved that the RSV transcreating gene (designated v-src) was homologous to a host cellular gene (c-src) that was widely conserved in eukaryotic species.16 Studies of many kind of various other acutely transforming retrovirsupplies from fowl, rodent, feline, and also nonhuman primate species have caused the discovery of dozens of various retroviral oncogenes (see listed below and also Table 6-1). In eincredibly case, these retroviral oncogenes are derived from normal cellular genes caught from the genome of the hold. Viral oncogenes are responsible for the fast tumor formation and effective in vitro transformation task characteristic of acutely transcreating retroviruses.
Retroviral transduction. A ribonucleic acid (RNA) tumor virus infects a huguy cell moving an triggered src gene (red star). After the process of recombicountry in between retroviral genome and organize deoxyribonucleic acid (DNA), the oncogene c-src is incorporated (more...)
In contrast to acutely transforming retrovirprovides, weakly oncogenic retrovirprovides perform not carry viral oncogenes. These retroviruses, which incorporate computer mouse mammary tumor virus (MMTV) and miscellaneous pet leukemia virsupplies, induce tumors by a process referred to as insertional mutagenesis (Figure 6-2).8 This process outcomes from integration of the DNA provirus right into the hold genome in infected cells. In rare cells, the provirus inserts close to a protooncogene. Expression of the protooncogene is then abcommonly driven by the transcriptional regulatory elements consisted of within the lengthy terminal repeats of the provirus.17,18 In these instances, proviral integration represents a mutagenic event that activates a protooncogene. Activation of the protooncogene then results in transformation of the cell, which can thrive clonally into a tumor. The long latent period of tumor formation of weakly oncogenic retrovirsupplies is therefore as a result of the rarity of the provirus insertional event that leads to tumor development from a solitary transformed cell. Insertional mutagenesis by weakly oncogenic retroviroffers, first demonstrated in bursal lymphomas of chickens, generally entails the exact same oncogenes (such as myc, myb, and also erb B) that are brought by acutely transdeveloping retrovirsupplies.19–21 In many type of cases, however, insertional mutagenesis has actually been offered as a tool to recognize new oncogenes, consisting of int-1, int-2, pim-1, and also lck.22
Insertional mutagenesis. A, The procedure is independent of genes carried by the retrovirus. Retrovirus, for example, computer mouse mammary tumor virus (MMTV), infects a humale cell. The proviral deoxyribonucleic acid (DNA) is incorporated into the host genome in (more...)
The demonstration of activated protooncogenes in humale tumors was initially shown by the DNA-mediated transdevelopment strategy.23,24 This strategy, additionally dubbed gene transfer or transfection assay, verifies the capacity of donor DNA from a tumor to transcreate a recipient strain of rodent cells called NIH 3T3, an immortalized mouse cell line (Figure 6-3).25,26 This sensitive assay, which deserve to detect the presence of single-copy oncogenes in a tumor sample, also permits the isolation of the transforming oncogene by molecular cloning techniques. After serial expansion of the transcreated NIH 3T3 cells, the huguy tumor oncogene deserve to be cloned by its association through human repetitive DNA sequences. The first huguy oncogene isolated by the gene carry technique was acquired from a bladder carcinoma.27,28 Overall, approximately 20% of individual human tumors have been displayed to induce transdevelopment of NIH 3T3 cells in gene-carry asstates. The value of transfection assay was recently reincompelled by the laboratory of Robert Weinberg, which verified that the ectopic expression of the telomerase catalytic subunit (hTERT), in combicountry with the simian virus 40 large T product and a mutated oncogenic H-ras protein, resulted in the straight tumorigenic convariation of normal huguy epithelial and also fibroblast cells.29 Many kind of of the oncogenes figured out by gene-carry studies are the same or very closely regarded those oncogenes transduced by retrovirsupplies. Most significant among these are members of the ras family that have actually been repeatedly isolated from miscellaneous human tumors by gene move.30,31 A variety of brand-new oncogenes (such as neu, met, and also trk) have likewise been determined by the gene-deliver approach.32,33 In many kind of cases, however, oncogenes determined by gene move were shown to be set off by resetup in the time of the experimental procedure and are not set off in the humale tumors that offered as the source of the donor DNA, as in the case of ret that was consequently discovered genuinely rearranged and set off in papillary thyroid carcinomas.34–36
Transfection assay. Deoxyribonucleic acid (DNA) from a tumor (eg, bladder carcinoma) was supplied to transdevelop a rodent immortalized cell line (NIH 3T3). After serial cycles, DNA from transcreated cells was extracted and then placed right into λ vector, (more...)
Chromosomal transplaces have actually offered as guidearticles for the exploration of many new oncogenes.37,38 Consistently recurring karyotypic abnormalities are uncovered in many type of hematologic and solid tumors. These abnormalities include chromosomal rearrangements as well as the obtain or loss of totality chromosomes or chromosome segments. The first continual karyotypic abnormality identified in a human neoplasm was a characteristic small chromosome in the cells of patients via chronic myelogenous leukemia.39 Later established as a derivative of chromosome 22, this abnormality was designated the Philadelphia chromosome, after its city of exploration. The application of chromosome banding methods in the early 1970s permitted the precise cytogenetic characterization of many chromosomal transareas in humale leukemia, lymphoma, and also solid tumors.40 The succeeding development of molecular cloning methods then enabled the identification of protooncogenes at or close to chromosomal breakpoints in assorted neoplasms. Some of these protooncogenes, such as myc and also abl, had been formerly figured out as retroviral oncogenes. In general, but, the cloning of chromosomal breakpoints has served as a well-off resource of discovery of brand-new oncogenes affiliated in humale cancer.
Oncogenes, protooncogenes, and their functions
Protooncogenes encode proteins that are associated in the manage of cell growth. Alteration of the structure and/or expression of protooncogenes can activate them to end up being oncogenes capable of inducing in at risk cells the neoplastic phenoform. Oncogenes can be classified right into five teams based upon the sensible and also biochemical properties of protein products of their normal counterparts (proto-oncogenes). These teams are (1) expansion factors, (2) development element receptors, (3) signal transducers, (4) transcription factors, and also (5) others, consisting of programmed cell fatality regulators. Table 6-1 lists examples of oncogenes according to their functional categories.
Growth determinants are secreted polypeptides that attribute as extracellular signals to stimulate the proliferation of targain cells.41,42 Appropriate target cells should possess a details receptor in order to respond to a details form of growth variable. A well-defined example is platelet-acquired expansion factor (PDGF), an around 30 kDa protein consisting of 2 polypeptide chains.43 PDGF is released from plateallows in the time of the procedure of blood coagulation. PDGF stimulates the proliferation of fibroblasts, a cell development process that plays a vital function in wound healing. Other well-defined examples of development components include nerve expansion factor, epidermal expansion variable, and also fibroblast growth factor.
The link between growth factors and also retroviral oncogenes was revealed by study of the sis oncogene of simian sarcoma virus, a retrovirus initially isolated from a monvital fibrosarcoma. Sequence analysis proved that sis encodes the beta chain of PDGF.44 This exploration establiburned the principle that inas necessary expressed development factors can function as oncogenes. Experiments demonstrated that the constitutive expression of the sis gene product (PDGF-β) was enough to cause neoplastic transformation of fibroblasts however not of cells that lacked the receptor for PDGF.45 Thus, transdevelopment by sis needs interaction of the sis gene product with the PDGF receptor. The device by which a growth element affects the very same cell that produces it is called autocrine stimulation .46 The constitutive expression of the sis gene product appears to cause neoplastic transdevelopment by the device of autocrine stimulation, leading to self-continual aberrant cell proliferation. This design, derived from experimental pet units, has actually been recently demonstrated in a humale tumor. Dermatofibrosarcoma protuberans (DP) is an infiltrative skin tumor that was demonstrated to existing particular cytogenetic features: reciprocal translocation and also supernumerary ring chromosomes, involving chromosomes 17 and also 22.47,48 Molecular cloning of the breakpoints revealed a combination in between the collagen form Ia1 (COL1A1) gene and also PDGF-β gene. The fusion gene caused a deletion of PDGF-β exon 1 and a constitutive release of this expansion element.49 Subsequent experiments of gene move of DPs genomic DNA right into NIH 3T3 cells straight demonstrated the incident of an autocrine system by the human rearranged PDGF-b gene entailing the activation of the endogenous PDGF receptor.50,51 Another example of a development element that deserve to attribute as an oncogene is int-2, a member of the fibroblast expansion variable household. Int-2 is sometimes triggered in mouse mammary carcinomas by MMTV insertional mutagenesis.52
Growth Factor Receptors
Some viral oncogenes are transformed versions of normal growth element receptors that possess intrinsic tyrosine kinase activity.53 Receptor tyrosine kinases, as these growth variable receptors are jointly known, have a characteristic protein structure consisting of 3 principal domains: (1) the extracellular ligand-binding doprimary, (2) the transmembrane domajor, and (3) the intracellular tyrosine kinase catalytic domain (view Figure 6-2). Growth factor receptors are molecular makers that transmit indevelopment in a unidirectional fashion throughout the cell membrane. The binding of a growth element to the extracellular ligandbinding domajor of the receptor outcomes in the activation of the intracellular tyrosine kinase catalytic doprimary. The recruitment and also phosphorylation of specific cytoplasmic proteins by the caused receptor then create a series of biochemical events mostly bring about cell department.
Since of the function of expansion factor receptors in the regulation of normal cell growth, it is not surprising that these receptors constitute a vital class of protooncogenes. Examples incorporate erb B, erb B-2, fms, kit, met, ret, ros, and trk. Mutation or abnormal expression of development aspect receptors can transform them into oncogenes.54 For instance, deletion of the ligand-binding domain of erb B (the epidermal expansion element receptor) is thneed to lead to constitutive activation of the receptor in the absence of ligand binding.55 Point mutation in the tyrosine kinase doprimary or of the extracellular domajor and deletion of intracellular regulatory domain names can also lead to the constitutive activation of receptor tyrosine kinases. Increased expression via gene amplification and also abnormal expression in the wrong cell type are added mechanisms with which expansion aspect receptors may be involved in neoplasia. The identification and also study of altered growth element receptors in speculative models of neoplasia have added a lot to our understanding of the normal regulation of cell proliferation.
Mitogenic signals are transmitted from development factor receptors on the cell surface to the cell nucleus with a series of facility interlocking pathmethods jointly referred to as the signal transduction cascade.56 This relay of information is achieved in component by the stepwise phosphorylation of connecting proteins in the cytosol. Signal transduction additionally involves guanine nucleotide-binding proteins and second messengers such as the adenylate cyclase device.57 The initially retroviral oncogene uncovered, src, was ultimately presented to be associated in signal transduction.
Many protooncogenes are members of signal transduction pathmeans.58,59 These consist of 2 major groups: nonreceptor protein kinases and also guanosine triphosphate (GTP)-binding proteins. The nonreceptor protein kinases are subclassified right into tyrosine kinases (eg, abl, lck, and also src) and serine/threonine kinases (eg, raf-1, mos, and also pim-1). GTP-binding proteins through intrinsic GTPase activity are subdivided right into monomeric and heterotrimeric teams.60 Monomeric GTP-binding proteins are members of the vital ras household of protooncogenes that consists of H-ras, K-ras, and N-ras.61 Heterotrimeric GTP-binding proteins (G proteins) implicated as protooncogenes currently include gsp and gip. Signal transducers are often converted to oncogenes by mutations that cause their unregulated task, which subsequently leads to unregulated cellular proliferation.62
Transcription components are nuclear proteins that control the expression of tarobtain genes or gene households.63 Transcriptional regulation is mediated by protein binding to certain DNA sequences or DNA structural motifs, commonly situated upstream of the tarobtain gene. Transcription determinants often belong to multigene family members that share prevalent DNA-binding domain names such as zinc fingers. The system of action of transcription factors additionally requires binding to other proteins, periodically in heterodimeric complexes via certain partners. Transcription components are the final link in the signal transduction pathway that converts extracellular signals into modulated changes in gene expression.
Many protooncogenes are transcription components that were discovered via their retroviral homologs.64 Examples encompass erb A, ets, fos, jun, myb, and c-myc. With Each Other, fos and jun create the AP-1 transcription variable, which positively regulates a variety of targain genes whose expression leads to cell division.65,66 Erb A is the receptor for the T3 thyroid hormone, triiodothyronine.67 Protooncogenes that attribute as transcription determinants are often activated by chromosomal translocations in hematologic and solid neoplasms.68 In specific kinds of sarcomas, chromosomal transareas cause the formation of fusion proteins involving the association of EWS gene through assorted partners and also causing an aberrant tumor-associated transcriptional task. Interestingly, a duty of the adenovirus E1A gene in promoting the formation of fusion transcript fli1/ews in normal humale fibroblasts was recently reported.69 An necessary instance of a protooncogene via a transcriptional activity in huguy hematologic tumors is the c-myc gene, which helps to control the expression of genes resulting in cell proliferation.70 As will be debated later in this chapter, the cmyc gene is frequently set off by chromosomal translocations in human leukemia and lymphoma.
Programmed Cell Death Regulation
Normal tworries exhilittle bit a regulated balance in between cell proliferation and also cell death. Programmed cell fatality is a crucial component in the processes of normal embryogenesis and organ breakthrough. A distinctive form of programmed cell fatality, dubbed apoptosis, has been described for mature tissues.71 This process is identified morphologically by blebbing of the plasma membrane, volume contraction, condensation of the cell nucleus, and also cleavage of genomic DNA by endogenous nucleases into nucleosome-sized pieces. Apoptosis can be triggered in mature cells by external stimuli such as steroids and radiation exposure. Studies of cancer cells have actually presented that both uncontrolled cell proliferation and faiattract to undergo programmed cell death can contribute to neoplasia and also insensitivity to anticancer therapies.
The only protooncogene therefore far presented to manage programmed cell death is bcl-2. Bcl-2 was found by the examine of chromosomal transplaces in humale lymphoma.72,73 Experipsychological researches display that bcl-2 activation inhibits programmed cell death in lymphoid cell populaces.74 The leading mode of action of triggered bcl-2 classifies it as an oncogene. The bcl-2 gene encodes a protein localized to the inner mitochondrial membrane, endoplasmic reticulum, and also nuclear membrane. The system of activity of the bcl-2 protein has not been completely elucidated, however studies indicate that it attributes in component as an antioxidant that inhibits lipid peroxidation of cell membranes.75 The normal function of bcl-2 calls for interactivity with various other proteins, such as bax, additionally thshould be associated in the regulation of programmed cell fatality (Figure 6-4). It is unmost likely that bcl-2 is the only apoptosis gene connected in neoplasia although additional protooncogenes await identification.
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Effect of bcl-2 activity on the control of the cell life. In the existence of BAX just, the cell goes to apoptosis; bcl-2 regulates the cycle of the cell by the interactivity via BAX. When bcl-2 is overexpressed, the cell cycle is deregulated and the apoptosis (even more...)
By agreement with the publisher, this book is available by the search attribute, yet cannot be browsed.