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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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Discovery and identification the oncogenes

Marco A. Pierotti, PhD, Gabriella Sozzi, PhD, and also Carlo M. Croce, MD.

The an initial oncogenes were uncovered through the study of retroviruses, RNA tumor viruses whose genomes space reverse-transcribed into DNA in infected pet cells.9 throughout the course of infection, retroviral DNA is inserted into the chromosomes of host cells. The incorporated retroviral DNA, referred to as the provirus, replicates together with the moving DNA that the host.10 warrior of the DNA provirus leader to the manufacturing of viral progeny that bud with the organize cell membrane come infect other cells. 2 categories the retroviruses are classified by your time course of tumor development in speculative animals. Acutely transforming retroviruses deserve to rapidly cause tumors in ~ days after ~ injection. This retroviruses can additionally transform cell societies to the neoplastic phenotype. Chronic or weakly oncogenic retroviruses can cause tissue-specific tumors in vulnerable strains that experimental animals after a latency duration of plenty of months. Back weakly oncogenic retroviruses can replicate in vitro, this viruses do not transform cells in culture.

Retroviral oncogenes are transformed versions of hold cellular protooncogenes that have actually been integrated into the retroviral genome by recombination with organize DNA, a process known together retroviral transduction.11 This surprising discovery was make through research of the Rous sarcoma virus (RSV) (Figure 6-1). RSV is one acutely transforming retrovirus an initial isolated indigenous a chicken sarcoma over 80 years back by Peyton Rous.12 researches of RSV mutants in the early 1970s revealed that the transforming gene that RSV to be not forced for viral replication.13–15 molecular hybridization research studies then verified that the RSV transforming gene (designated v-src) to be homologous come a organize cellular gene (c-src) the was commonly conserved in eukaryotic bio species.16 studies of numerous other acutely transforming retroviruses indigenous fowl, rodent, feline, and also nonhuman primate varieties have resulted in the discovery of dozens of various retroviral oncogenes (see below and Table 6-1). In every case, these retroviral oncogenes are derived from regular cellular genes caught from the genome the the host. Famous oncogenes room responsible because that the rapid tumor formation and efficient in vitro revolution activity characteristics of acutely transforming retroviruses.


Figure 6-1

Retroviral transduction. A ribonucleic acid (RNA) tumor virus infects a human cell delivering an set off src gene (red star). ~ the process of recombination between retroviral genome and also host deoxyribonucleic mountain (DNA), the oncogene c-src is included (more...)


In comparison to acutely transforming retroviruses, weakly oncogenic retroviruses carry out not carry viral oncogenes. This retroviruses, which encompass mouse mammary tumor virus (MMTV) and various pet leukemia viruses, induce tumors by a procedure called insertional mutagenesis (Figure 6-2).8 This procedure results from integration the the DNA provirus right into the host genome in infected cells. In rarely cells, the provirus inserts close to a protooncogene. Expression of the protooncogene is climate abnormally driven by the transcriptional regulatory facets contained in ~ the long terminal repeats of the provirus.17,18 In this cases, proviral integration represents a mutagenic event that activates a protooncogene. Activation the the protooncogene then outcomes in revolution of the cell, which can thrive clonally into a tumor. The lengthy latent period of tumor development of weakly oncogenic retroviruses is thus due come the rarity that the provirus insertional occasion that leader to tumor development from a solitary transformed cell. Insertional mutagenesis through weakly oncogenic retroviruses, an initial demonstrated in bursal lymphomas the chickens, generally involves the same oncogenes (such as myc, myb, and erb B) that are brought by acutely transforming retroviruses.19–21 In many cases, however, insertional mutagenesis has been supplied as a tool to identify new oncogenes, including int-1, int-2, pim-1, and also lck.22


Figure 6-2

Insertional mutagenesis. A, The procedure is independent of genes brought by the retrovirus. Retrovirus, for example, mouse mammary tumor virus (MMTV), infects a person cell. The proviral deoxyribonucleic acid (DNA) is incorporated into the hold genome in (more...)

The demonstrate of triggered protooncogenes in person tumors was an initial shown by the DNA-mediated change technique.23,24 This technique, likewise called gene transfer or transfection assay, verifies the capacity of donor DNA native a tumor to transform a recipient strain of rodent cells referred to as NIH 3T3, an immortalized computer mouse cell heat (Figure 6-3).25,26 This sensitive assay, which can detect the visibility of single-copy oncogenes in a tumor sample, also allows the isolation that the transforming oncogene by molecular cloning techniques. After ~ serial growth of the revolutionized NIH 3T3 cells, the human tumor oncogene can be cloned by its association with human being repetitive DNA sequences. The an initial human oncogene secluded by the gene transfer technique was obtained from a bladder carcinoma.27,28 Overall, approximately 20% that individual human being tumors have been shown to induce transformation of NIH 3T3 cells in gene-transfer assays. The value of transfection assay was freshly reinforced by the activities of Robert Weinberg, which verified that the ectopic expression of the telomerase catalytic subunit (hTERT), in combination with the simian virus 40 large T product and a mutated oncogenic H-ras protein, resulted in the direct tumorigenic conversion of normal human being epithelial and also fibroblast cells.29 numerous of the oncogenes figured out by gene-transfer studies are similar or carefully related to those oncogenes transduced by retroviruses. Many prominent among these space members that the ras family that have been repetitively isolated indigenous various person tumors by gene transfer.30,31 A number of new oncogenes (such as neu, met, and also trk) have likewise been figured out by the gene-transfer technique.32,33 In countless cases, however, oncogenes figured out by gene carry were presented to be activated by rearrangement throughout the experimental procedure and also are not triggered in the person tumors that offered as the source of the donor DNA, together in the instance of ret the was subsequently found genuinely rearranged and also activated in papillary thyroid carcinomas.34–36


Figure 6-3

Transfection assay. Deoxyribonucleic mountain (DNA) native a tumor (eg, bladder carcinoma) was offered to change a rodent immortalized cell heat (NIH 3T3). After ~ serial cycles, DNA from changed cells was extracted and then put into λ vector, (more...)

Chromosomal translocations have served as guideposts because that the discovery of many brand-new oncogenes.37,38 repeatedly recurring karyotypic abnormalities are uncovered in countless hematologic and also solid tumors. These abnormalities include chromosomal rearrangements as well as the acquire or ns of entirety chromosomes or chromosome segments. The an initial consistent karyotypic abnormality figured out in a human being neoplasm was a characteristic small chromosome in the cell of patients through chronic myelogenous leukemia.39 Later figured out as a derivative that chromosome 22, this abnormality was designated the Philadelphia chromosome, after its city of discovery. The applications of chromosome banding techniques in the at an early stage 1970s permitted the precise cytogenetic characterization of numerous chromosomal translocations in human leukemia, lymphoma, and also solid tumors.40 The subsequent advance of molecular cloning approaches then allowed the identification of protooncogenes in ~ or near chromosomal breakpoints in miscellaneous neoplasms. Few of these protooncogenes, such together myc and also abl, had actually been previously figured out as retroviral oncogenes. In general, however, the cloning the chromosomal breakpoints has actually served as a rich source of exploration of brand-new oncogenes connected in person cancer.

Oncogenes, protooncogenes, and also their functions

Protooncogenes encode proteins the are involved in the manage of cell growth. Alteration of the framework and/or expression the protooncogenes can activate them to end up being oncogenes qualified of inducing in susceptible cells the neoplastic phenotype. Oncogenes have the right to be share into 5 groups based on the functional and also biochemical nature of protein products of their normal counterparts (proto-oncogenes). These groups are (1) development factors, (2) expansion factor receptors, (3) signal transducers, (4) warrior factors, and also (5) others, including programmed cell death regulators. Table 6-1 lists examples of oncogenes according to their useful categories.

Growth Factors

Growth factors are secreted polypeptides that role as extracellular signals to wake up the proliferation of target cells.41,42 suitable target cells should possess a specific receptor in order come respond to a specific form of development factor. A well-characterized example is platelet-derived development factor (PDGF), an approximately 30 kDa protein consists of 2 polypeptide chains.43 PDGF is released from platelets throughout the process of blood coagulation. PDGF stimulates the proliferation that fibroblasts, a cabinet growth procedure that plays an essential role in wound healing. Other well-characterized instances of growth determinants include nerve development factor, epidermal development factor, and fibroblast expansion factor.

The link in between growth factors and also retroviral oncogenes to be revealed by examine of the sis oncogene that simian sarcoma virus, a retrovirus very first isolated native a monkey fibrosarcoma. Sequence analysis showed the sis encodes the beta chain the PDGF.44 This discovery developed the principle the inappropriately to express growth components could function as oncogenes. Experiments demonstrated the the constitutive expression of the sis gene product (PDGF-β) was sufficient to cause neoplastic change of fibroblasts however not that cells the lacked the receptor because that PDGF.45 Thus, change by sis requires communication of the sis gene product with the PDGF receptor. The mechanism through which a expansion factor affects the same cell the produces the is dubbed autocrine stimulation .46 The constitutive expression that the sis gene product appears to reason neoplastic transformation by the system of autocrine stimulation, causing self-sustained aberrant cell proliferation. This model, derived from experimental animal systems, has actually been recently demonstrated in a person tumor. Dermatofibrosarcoma protuberans (DP) is an infiltrative skin tumor the was prove to present specific cytogenetic features: mutual translocation and also supernumerary ring chromosomes, including chromosomes 17 and also 22.47,48 molecule cloning the the breakpoints revealed a blend between the collagen form Ia1 (COL1A1) gene and also PDGF-β gene. The fusion gene led to a deletion the PDGF-β exon 1 and also a constitutive relax of this development factor.49 subsequent experiments the gene transport of DPs genomic DNA right into NIH 3T3 cells directly demonstrated the occurrence of an autocrine system by the human being rearranged PDGF-b gene entailing the activation of the endogenous PDGF receptor.50,51 another example that a growth factor the can role as one oncogene is int-2, a member the the fibroblast expansion factor family. Int-2 is sometimes activated in mouse mammary carcinomas by MMTV insertional mutagenesis.52

Growth element Receptors

Some viral oncogenes are transformed versions that normal development factor receptors that possess intrinsic tyrosine kinase activity.53 Receptor tyrosine kinases, as these expansion factor receptor are jointly known, have a properties protein framework consisting that three primary domains: (1) the extracellular ligand-binding domain, (2) the transmembrane domain, and also (3) the intracellular tyrosine kinase catalytic domain (see number 6-2). Expansion factor receptors are molecular devices that transmit information in a unidirectional fashion throughout the cabinet membrane. The binding the a growth factor come the extracellular ligandbinding domain that the receptor results in the activation of the intracellular tyrosine kinase catalytic domain. The recruitment and phosphorylation of certain cytoplasmic protein by the triggered receptor then cause a collection of biochemical events generally causing cell division.

Because of the duty of development factor receptors in the regulation of regular cell growth, that is not surprising that these receptors constitute crucial class that protooncogenes. Examples include erb B, erb B-2, fms, kit, met, ret, ros, and trk. Mutation or abnormal expression of development factor receptor can transform them into oncogenes.54 because that example, deletion the the ligand-binding domain the erb B (the epidermal growth factor receptor) is assumed to an outcome in constitutive activation of the receptor in the lack of ligand binding.55 point mutation in the tyrosine kinase domain or the the extracellular domain and deletion the intracellular regulatory domain names can also result in the constitutive activation of receptor tyrosine kinases. Enhanced expression v gene amplification and abnormal expression in the wrong cell type are added mechanisms with which growth factor receptors might be connected in neoplasia. The identification and study of changed growth variable receptors in speculative models the neoplasia have added much to our knowledge of the common regulation of cell proliferation.

Signal Transducers

Mitogenic signals room transmitted from development factor receptors on the cell surface ar to the cell nucleus with a series of complicated interlocking pathways jointly referred to as the signal transduction cascade.56 This relay of information is completed in component by the stepwise phosphorylation of communicating proteins in the cytosol. Signal transduction additionally involves guanine nucleotide-binding protein and 2nd messengers such as the adenylate cyclase system.57 The very first retroviral oncogene discovered, src, was subsequently presented to be connected in signal transduction.

Many protooncogenes space members that signal transduction pathways.58,59 this consist that two key groups: nonreceptor protein kinases and also guanosine triphosphate (GTP)-binding proteins. The nonreceptor protein kinases room subclassified right into tyrosine kinases (eg, abl, lck, and src) and also serine/threonine kinases (eg, raf-1, mos, and also pim-1). GTP-binding proteins v intrinsic GTPase task are subdivided into monomeric and also heterotrimeric groups.60 Monomeric GTP-binding proteins are members of the important ras household of protooncogenes that consists of H-ras, K-ras, and N-ras.61 Heterotrimeric GTP-binding protein (G proteins) implicated as protooncogenes currently include gsp and gip. Signal transducers are frequently converted to oncogenes by mutations that bring about their control not controlled activity, which consequently leads to uncontrolled cellular proliferation.62

Transcription Factors

Transcription factors are atom proteins that manage the expression of target gene or gene families.63 Transcriptional regulation is mediated by protein binding to specific DNA order or DNA structure motifs, usually situated upstream that the target gene. Transcription determinants often belong come multigene households that share usual DNA-binding domains such as zinc fingers. The system of activity of warrior factors additionally involves binding to various other proteins, sometimes in heterodimeric complexes with certain partners. Transcription determinants are the final connect in the signal transduction pathway the converts extracellular signals right into modulated transforms in gene expression.

Many protooncogenes room transcription components that were discovered through your retroviral homologs.64 Examples include erb A, ets, fos, jun, myb, and also c-myc. Together, fos and also jun kind the AP-1 transcription factor, which positive regulates a number of target gene whose expression leader to cabinet division.65,66 Erb A is the receptor because that the T3 thyroid hormone, triiodothyronine.67 Protooncogenes that duty as transcription determinants are often activated through chromosomal translocations in hematologic and solid neoplasms.68 In certain varieties of sarcomas, chromosomal translocations reason the formation of combination proteins involving the combination of EWS gene with assorted partners and also resulting in an aberrant tumor-associated transcriptional activity. Interestingly, a function of the adenovirus E1A gene in fostering the development of fusion transcript fli1/ews in normal human fibroblasts was recently reported.69 an essential example that a protooncogene through a transcriptional activity in human being hematologic tumors is the c-myc gene, which help to manage the expression of genes resulting in cell proliferation.70 As will be questioned later in this chapter, the cmyc gene is generally activated through chromosomal translocations in human being leukemia and lymphoma.

Programmed Cell fatality Regulation

Normal organization exhibit a regulation balance between cell proliferation and cell death. Programmed cell fatality is crucial component in the processes of normal embryogenesis and also organ development. A distinctive type of programmed cell death, dubbed apoptosis, has actually been described for maturation tissues.71 This procedure is identified morphologically by blebbing the the plasma membrane, volume contraction, condensation that the cell nucleus, and cleavage the genomic DNA by endogenous nucleases right into nucleosome-sized fragments. Apoptosis have the right to be prompted in mature cell by external stimuli such as steroids and also radiation exposure. Studies of cancer cell have shown that both untreated cell proliferation and failure to undergo programmed cell death can contribute to neoplasia and insensitivity come anticancer treatments.

The only protooncogene hence far displayed to regulate programmed cell fatality is bcl-2. Bcl-2 was found by the examine of chromosomal translocations in human lymphoma.72,73 speculative studies present that bcl-2 activation inhibits programmed cell fatality in lymphoid cell populations.74 The leading mode of activity of triggered bcl-2 classifies it as an oncogene. The bcl-2 gene encodes a protein localized come the inner mitochondrial membrane, absorbent reticulum, and nuclear membrane. The system of activity of the bcl-2 protein has not been fully elucidated, yet studies suggest that it attributes in component as one antioxidant that inhibits lipid peroxidation of cabinet membranes.75 The normal role of bcl-2 requires communication with various other proteins, such together bax, likewise thought come be involved in the regulation the programmed cell fatality (Figure 6-4). The is unlikely that bcl-2 is the only apoptosis gene associated in neoplasia although extr protooncogenes await identification.

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Figure 6-4

Effect the bcl-2 task on the manage of the cabinet life. In the existence of BAX only, the cabinet goes come apoptosis; bcl-2 regulates the bicycle of the cabinet by the communication with BAX. When bcl-2 is overexpressed, the cell cycle is deregulated and also the apoptosis (more...)

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