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Oncogenes

  1. Amanda R Perry

Published Online: 19 APR 2001

DOI: 10.1038/npg.els.0001474

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Perry, A. R. 2001. Oncogenes. eLS.

Author Information

  1. Institute of Cancer Research, Sutton, Surrey, UK

Publication History

  1. Published Online: 19 APR 2001

Introduction

  1. Top of page
  2. Introduction
  3. Viral-induced Tumours
  4. Viral Oncogenes
  5. Cellular Oncogenes
  6. Normal Functions of Oncogenes
  7. Therapeutic Prospects
  8. Summary
  9. References
  10. Further Reading

As study of the molecular and cellular basis of cancer progresses, it is becoming clear that no two cancers are identical: tumour development is a complex process, and there are many paths to malignancy. Nevertheless, certain tenets persist: that cancer arises as the result of genetic change; that this leads to loss of control over cellular proliferation, and that usually several genetic errors are required to reach the full neoplastic phenotype. Deregulated cellular proliferation may arise in two main ways: through the loss of genes that normally check cell growth (the tumour suppressors) or by the gain of function of genes that either promote cellular proliferation or prevent cell death (the oncogenes) (from Greek onkos, tumour). Some cancer-associated genes, for example those involved in DNA repair, do not fall easily into either category; others such as P53 are tumour suppressors in wild-type form, but can act as dominant oncogenes in certain mutant forms. In many instances of adult human cancer, both features – oncogenic activation and loss of tumour suppressor activity – may be identified. See also Cancer, Tumour Suppressor Genes, DNA Repair Disorders, DNA Repair, and Li–Fraumeni Syndrome

A typical oncogene has dominant activity, and requires only one allele to be activated in order to be oncogenic. An oncogene may be viral or cellular in origin; a viral oncogene may be unique to the virus, or a homologue of a cellular ‘proto-oncogene’. An oncogene can promote transformation in vitro, and tumour formation in transgenic animals; further, its deregulation is usually recurrently associated with malignancy. Of over a hundred oncogenes that have been described, many are not entirely typical, but the model remains useful.

Viral-induced Tumours

  1. Top of page
  2. Introduction
  3. Viral-induced Tumours
  4. Viral Oncogenes
  5. Cellular Oncogenes
  6. Normal Functions of Oncogenes
  7. Therapeutic Prospects
  8. Summary
  9. References
  10. Further Reading

The concept of cancer-causing genes arose from early observations that viruses can induce tumour formation in animals. Both retroviruses and DNA viruses can carry oncogenes, which often resemble cellular genes. Viruses may also induce tumours through integration into the host genome, bringing a cellular gene under control of a viral promoter, or a virus may promote tumour formation through its suppressive effect on the host immune system. Despite these varied mechanisms, the contribution viruses make to cancer in human and animal populations is relatively small, although the discovery of virally induced tumours has had far-reaching implications for our understanding of oncogenes. See also Oncogenic Viruses

Retroviruses

Pioneering work on retroviral tumours was performed in the early part of the twentieth century, particularly by Peyton Rous who described the Rous sarcoma virus (RSV), that induced tumour formation in chickens. RSV is a typical acute retrovirus, an RNA virus that copies its RNA to DNA by reverse transcription after infection of a cell. The DNA is inserted into the host genome, where it can persist and be inherited by subsequent cell generations. Work on RSV and other acute retroviruses demonstrated not only tumour formation by the viruses, but their ability to transform fibroblasts (Martin, 1970). Transformation is an in vitro phenomenon which has proved a useful assay for oncogenic viruses – and oncogenes themselves. Transformed cells do not respond to growth inhibitory signals such as cell–cell contact, and they have less requirement for growth factors than their untransformed counterparts. They are ‘immortal’, in that they can proliferate indefinitely, and have an unusually rounded morphology. They thus appear as fast-growing colonies of rounded cells which can be quantified on a culture plate. Studies on a form of mutant RSV that failed to induce transformation led to the identification of the first viral oncogene, src (Martin, 1970). See also Rous, Francis Peyton, Retroviral Replication, and Primary Cell Cultures and Immortal Cell Lines

Oncogenes like src are thought to have been captured from the host genome during viral integration, although they have often undergone mutation during their viral passage. While retroviral oncogenes thus have cellular counterparts, the context in which they are carried renders them oncogenic. They are driven by the promoter within the retroviral long terminal repeat (LTR), which produces unregulated, often higher, expression than the normal cellular genes (Figure 1). Furthermore, retroviral oncogenes may encode proteins with properties different to those of the cellular proteins, as a result of mutation. Importantly, retroviral oncogenes are unnecessary for replication of the virus. Indeed, they often carry a survival disadvantage as a result of tumour induction, and in all likelihood are maintained artificially within the experimental environment, with low natural prevalence or significance. See also Genome Organization: Human, and RNA Virus Genomes

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Figure 1. Mechanisms of oncogene activation. LTR, long terminal repeat.

Chronic retroviruses generally induce tumour formation by the alternative mechanism of gene insertion, whereby random insertion of the viral genome into the host genome can cause activation of cellular genes, causing them to become oncogenic (Figure 1). Because the process of gene activation is random, and because the resulting gene activation is often lethal for the cell, it can take many years for a tumour to be induced by chronic retroviral infection.

Viral tumours in humans

There are a small number of human malignancies in which a viral aetiology has been demonstrated, or strongly suspected. However, no acute retrovirus has been associated with any human tumour, and only two chronic retroviruses are linked to cancer in humans. Human immunodeficiency virus (HIV) is associated with a number of malignancies through its immunosuppressive effects, which prevent an adequate T-cell response to malignant cells. This is particularly marked when the malignant cells are expressing foreign antigens, for example from other viruses, which would normally provoke a host response. Moreover, HIV can have a more direct effect on tumour formation by inducing capillary growth, contributing to the pathogenesis of Kaposi sarcoma and perhaps facilitating spread of other tumours. Human T cell leukaemia virus type I (HTLV-I), another chronic retrovirus, has been identified as the aetiological agent of adult T-cell leukaemia, endemic in certain areas of the world including central Africa and the Caribbean basin. Only 1–4% of HTLV-I carriers develop T-cell leukaemia, and this only after a latency of 20–30 years. See also AIDS: Clinical Manifestations, and Human Immunodeficiency Viruses (HIV)

DNA viruses are also not commonly oncogenic in humans – surprisingly, given their frequency of infection in higher animals, and their tendency to promote cell proliferation. One reason is that malignant transformation confers no survival benefit to the virus. Second, DNA virus replication is accompanied by expression of immunogenic proteins, leading to destruction of the host cell. Where such virus-associated tumours are common, therefore, is in the context of impaired T-cell immunity. For example, tumours associated with immunosuppression due to HIV infection include Epstein–Barr virus (EBV)-associated lymphomas, Human herpes virus 8 (HHV-8)-positive Kaposi sarcoma, and anogenital carcinoma associated with Human papillomavirus (HPV) infection. Third, there are nonimmune mechanisms thought to operate within and between cells that suppress the function of viruses and their oncogene products. See also DNA Virus Genomes, Herpesviruses (Human), and Papillomaviruses

EBV is a lymphotropic herpesvirus, endemic in all human populations but only rarely associated with malignant change. Acute EBV infection can give rise to fatal lymphoproliferation of B cells, and indeed T cells, but only in the context of severe immunosuppression such as exists after bone marrow transplantation, or through rare genetic defects. Similarly, reactivation of latent EBV, leading to lymphoproliferative tumours, may occur with chronic immunosuppression, either iatrogenic (posttransplant) or virus-induced (AIDS-associated). In nonimmunosuppressed patients, Burkitt lymphoma and nasopharyngeal carcinoma have an established association with EBV. Burkitt lymphoma was long suspected to have an infectious cause, due to its geographically limited occurrence, and the link was initially demonstrated by electron microscopic observation of EBV particles in tumour cultures (Epstein et al., 1964). Some types of Hodgkin disease and some T-cell lymphomas also have an association with the virus. See also Epstein–Barr Virus and Cancer, and Leukaemias and Lymphomas

Other DNA viruses involved in human malignancy include HHV8, another herpesvirus identified from Kaposi sarcoma in acquired immune deficiency syndrome (AIDS) patients, now with an established role in the aetiology of this tumour (Moore and Chang, 1998). HPV, a DNA virus, has over 60 genotypes, 11 of which are associated with human cancers, HPV-16 and 18 being strongly associated with cervical and anal carcinomas. Similarly, Hepatitis B virus (HBV) was linked with hepatocellular carcinoma through seroepidemiological studies, and a closely related virus was isolated from woodchucks, which causes liver cancer (zur Hausen, 1999). However, the precise role that Hepatitis B virus plays in human liver cancer remains ill-defined, with no oncogenes being clearly identified. See also Hepatitis B Virus, and Hepatitis: Clinical Features and Treatment

Viral Oncogenes

  1. Top of page
  2. Introduction
  3. Viral-induced Tumours
  4. Viral Oncogenes
  5. Cellular Oncogenes
  6. Normal Functions of Oncogenes
  7. Therapeutic Prospects
  8. Summary
  9. References
  10. Further Reading

According to the model, a true viral oncogene demonstrates the ability to transform primary cells in vitro, although often cooperation between two oncogenes is required for efficient transformation. It should cause tumour formation in transgenic mice, and be associated with cancers, either in its viral form, or as deregulated expression of a cellular homologue. See also Tumorigenicity Assays

Retroviral oncogenes

It seems that all oncogenes carried by retroviruses have a cellular counterpart, although in many cases this has only been identified after discovery of the viral oncogene. Thus the RSV oncogene src has a cellular homologue, SRC. Despite the fact that RSV strains are not tumorigenic in mammals, mammalian fibroblasts can be transformed to a malignant phenotype by both src and SRC; further, increased SRC expression has been identified in some human cancers, including colon, skin and breast cancers (Hesketh, 1997). Table 1 shows other retroviral oncogenes, with their normal cell counterparts. See also Colon Cancer, Melanoma, and Breast Cancer

Table 1. Examples of retroviral oncogenes and their cellular homologues
RetrovirusViral oncogeneCellular homologue
Abelson murine leukaemia virusablABL
Avian erythroblastosis viruserbA, erbB, etsERBA, ERBB (EGFR), ETS
FBJ murine osteosarcoma virusfosFOS
Avian sarcoma virus-17junJUN
Avian myelocytomatosis virusmycMYC
Murine sarcoma virusH-ras, K-rasH-RAS, K-RAS
Rous sarcoma virussrcSRC

Viral oncogenes in humans

Of the virus-associated human tumours mentioned above, only EBV, HHV-8 and HPV possess clearly defined oncogenes. EBV is a complex virus with a large genome; in latent infections, about 11 viral genes are expressed, grouped into the nuclear antigens or EBNAs, and the latent membrane proteins or LMPs. EBNA1 induces tumours in transgenic animals, but not transformation in vitro; EBNA2 has transforming properties in vitro (Hesketh, 1997). It is likely that the oncogenic potential of EBV is the result of the combined contribution of several of these protein products, some of which activate cellular proliferative pathways, and others of which inhibit cell death. The HHV-8 genome also contains a number of potential oncogenes: here, the protein products are related to cyclin D, interleukins and interferon-responsive factors. Two oncoproteins, E6 and E7, are encoded within the genome of HPV types 16 and 18 (Figure 1); these interfere with the function of two important cellular tumour suppressors, p53 and Rb (zur Hausen, 1999). These oncogenes result in tumour formation in transgenic mice, and cooperate with cellular genes to transform fibroblasts in vitro. See also Epstein–Barr Virus, Cell Cycle, and Tumour Suppressor Genes

Other viral proteins contributing to human cancers are less typical in their role as oncoproteins, or await clearer definition of their function in tumour formation. HBV frequently shows integration during chronic infection, although this is not part of its life cycle. Cis-activation of adjacent cellular genes may result from such integration, while transactivating viral proteins such as pX may contribute to aberrant expression of cellular genes. HTLV-I similarly possesses the viral gene, tax, which transactivates the viral LTR through protein–protein interaction (Figure 1). In addition it can transactivate a number of cellular genes, including those encoding cytokines, cytokine receptors and transcription factors, and it is this function that is thought to contribute to malignant transformation. The tax gene cannot, however, induce transformation alone, and there may be other HTLV-I genes, and probably nonviral cellular events, necessary for inducing the malignant T-cell phenotype. Similarly, HIV does not carry a true oncogene, but it does carry the gene Tat that encodes a protein with angiogenic properties, inducing endothelial cell growth, migration and invasion in vitro. See also HIV Life Cycle and Inherited Co-receptors

Cellular Oncogenes

  1. Top of page
  2. Introduction
  3. Viral-induced Tumours
  4. Viral Oncogenes
  5. Cellular Oncogenes
  6. Normal Functions of Oncogenes
  7. Therapeutic Prospects
  8. Summary
  9. References
  10. Further Reading

Viruses have contributed greatly to the present understanding of oncogene function, but have had a less significant role in human oncogenesis. Most oncogenes involved in human tumours are not viral but cellular – genes that are present in the normal genome, which are deregulated or activated by mutation. There are three mechanisms of cellular oncogenic activation: (1) through alteration of the coding sequence by deletion or point mutation; (2) by increasing the copy number of the gene; and (3) by chromosomal rearrangement (Table 2). See also Genome Organization: Human

Table 2. Mechanisms of cellular oncogene activation
MalignancyOncogeneMutation
GlioblastomaEGFRAmplification
Breast carcinomaERB-B2Amplification
Breast carcinomaCCND1Amplification
NeuroblastomaERB-B2Point mutation
Pancreatic carcinomaRASPoint mutation
Colorectal carcinomaRASPoint mutation
Chronic myeloid leukaemiaBCR-ABLGene fusion
Burkitt lymphomaMYCIgH juxtaposition
Follicular lymphomaBCL2IgH juxtaposition
Mantle cell lymphomaCCND1IgH juxtaposition

Activation by alterations of the coding sequence

Point mutations and intragenic mutations arise as the result of DNA damage caused by chemical agents, or physical agents such as radiation (Figure 1). Because of base changes, the amino acid sequence of an encoded protein is altered, with a corresponding change in function. If the protein is a key player in growth or other signalling pathways, loss of function will have no effect (unless both alleles are affected – as in tumour suppressors), but gain of function may result in accelerated proliferation. A prime example is the Ras family of signalling molecules that become hyperactive as the result of single base substitutions, providing these occur at crucial points in the coding sequence. Activated RAS has been identified in many human tumours, including about 80% of pancreatic and 40% of colorectal carcinomas (Hesketh, 1997). Such mutations have been demonstrated to be inducible by chemical toxins or ultraviolet radiation, and there is a viral homologue of activated RAS, carried by the murine sarcoma virus. Activated RAS mediates transformation of fibroblasts in culture, and leads to tumour formation in transgenic animals (Hesketh, 1997). See also Mutations: Origin, Nature and Impact, DNA Damage, and G Proteins

Activation by gene amplification

Amplification as a route to oncogene activation is a poorly understood process in which several megabases of chromosomal material are typically copied in tandem, up to perhaps 50 or 100 times (Figure 1). The resulting DNA is then retained episomally (outside the normal cellular chromosomes), in which case cell division may result in unequal portions of replicated material being passed to the progeny, or it may be reintegrated within a chromosome. Such phenomena have never been described in nonmalignant tissues, and appear to be typical of solid tumours rather than haematological malignancies. Examples of oncogenes activated in this way include EGFR, NEU and CCND1, encoding the epidermal growth factor receptor (EGFR), the related erbB2 receptor and cyclin D1, respectively. See also Gene Amplification, and Chromosomes and Cancer

Activation by chromosomal rearrangement

Oncogenes may also be activated through chromosomal rearrangement, i.e. translocations, interstitial deletions or inversions. These tend to result in the gene being brought under new transcriptional control, leading to overexpression, or in the gene being truncated, making it hyperactive, or in the gene being fused to another, leading to a hybrid oncoprotein with functions combining those of both gene partners. Haematological malignancies are particularly associated with chromosomal rearrangements: a well-known example of a fusion gene results from the translocation of ABL on chromosome 9 to the BCR locus on 22. The result, BCR-ABL, produces a new Bcr-Abl fusion protein. This molecular change is very strongly associated with chronic myeloid leukaemia (CML) in which it is frequently the only abnormality. See also Chromosome Rearrangements, Chronic Myeloid Leukaemia, and Cancers, Familial

A typical translocation in lymphomas results in a variety of genes, often called B-cell leukaemia/lymphoma genes, (BCL-), being translocated near to one of the immunoglobulin loci, where they are brought under control of the immunoglobulin promoter and/or enhancer. Since the normal lymphocyte expresses high levels of immunoglobulin, any gene translocated to the same locality, such as MYC in Burkitt lymphoma; BCL2 in follicular lymphoma, or CCND1 in mantle cell lymphoma, will also be expressed at high levels. See also Leukaemias and Lymphomas

Virus-associated chromosomal rearrangements

The IgH-MYC translocation, together with similar translocations of MYC to the immunoglobulin light chain loci, are universal findings in Burkitt lymphoma, even in the sporadic cases where EBV is not involved. The close association between a chromosomal translocation and a viral oncogenic effect, however, remains something of a puzzle – are they separate phenomena, both important in the development of lymphoma? If so, non-EBV-related cases are more difficult to explain. Another speculative explanation has been that EBV increases the probability of specific gene translocation, either directly at the gene level, or indirectly by selecting for cells containing that translocation. Interestingly, it has recently been demonstrated that an adenovirus oncogene, E1A, specifically induces a fusion oncogene identical to that found in the human tumour Ewing sarcoma (Kirn and Hermiston, 1999).

Normal Functions of Oncogenes

  1. Top of page
  2. Introduction
  3. Viral-induced Tumours
  4. Viral Oncogenes
  5. Cellular Oncogenes
  6. Normal Functions of Oncogenes
  7. Therapeutic Prospects
  8. Summary
  9. References
  10. Further Reading

Both cellular oncogenes and most viral oncogenes derive from normal cellular genes or proto-oncogenes. These genes encode proteins that function in essential cellular pathways: in general, a proto-oncogene is likely to be pro-proliferative, and/or pro-survival, and/or an inhibitor of differentiation. These functions of a cell are governed by factors in the extracellular environment such as cell–cell contact and growth factors, and signals are relayed from the cell surface to the cell nucleus by signalling cascades. Proto-oncogenes may be divided into broad groups according to their position in such cascades: they may be growth factors; cell surface receptors; membrane transducers; intracellular signalling proteins or transcription factors. The pathways are complex, converging and diverging, and the endpoints – proliferation, survival and state of differentiation – are often interdependent. Nevertheless, even an incomplete understanding of normal proto-oncogene function provides insights into the role of oncogenes in tumorigenesis.

Growth factors and receptors

Cell surface receptors that function in growth regulation fall into several superfamilies. One of these includes the platelet-derived growth factor (PDGF) receptor, the ligand for which has an oncogenic homologue, SIS, which when overexpressed causes excessive signalling through the PDGF pathway. Another of the receptor tyrosine kinase families is the epidermal growth factor (EGF) receptor family. In this case, the gene encoding the EGF receptor itself is amplified in some human tumours (Hanahan and Weinberg, 2000), causing it to function as an oncogene. A related gene, NEU, is also overexpressed in tumours and has a viral homologue erbB, which encodes a truncated EGF receptor. In this form, the receptor is constitutively active, and does not require ligand binding to function. The EGF receptor, like most growth factor receptors, is a tyrosine kinase, signalling to downstream molecules through membrane-associated binding and phosphorylation (Figure 2). See also Signal Transduction: Overview

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Figure 2. The epidermal growth factor receptor (EGFR) signalling pathway.

Membrane transducers

Two important categories of protein that transmit signals from receptors to cytoplasmic molecules are the ‘non-receptor tyrosine kinases’ such as the protein encoded by SRC, and GTP-binding proteins or ‘G-proteins’, such as members of the Ras family. This family is comprised of closely related genes H-RAS, K-RAS and N-RAS, encoding proteins of 21 kDa (hence, p21ras). Each p21ras protein binds one molecule of guanosine triphosphate (GTP) or guanosine diphosphate (GDP); phosphorylation of bound GDP converts p21ras from ‘off’ mode to ‘on’ mode, mediating binding and activation of downstream regulators like Raf and MEK. RAS becomes oncogenic usually as the result of point mutations, which prevent the hydrolysis of p21ras-bound GTP, maintaining it permanently in the ‘on’ position. See also G Proteins

Serine/threonine kinases

Further downstream, many molecular mediators function as serine/threonine kinases, each kinase phosphorylating other kinases in cascade fashion. These include the protein product of AKT, the cellular homologue of an avian viral oncogene. The Akt protein is an important cytoplasmic kinase that lies downstream of several growth factor and cytokine receptors, and upstream of cell cycle and apoptotic regulators. See also Protein Kinases: Physiological Roles in Cell Signalling

Cell cycle regulators

The proliferation state of the cell is determined by its position in, and passage through, the cell cycle. Passage through the cycle is in turn governed by a number of proteins that take their cues from signalling cascades, allowing the cell to move from one stage to the next. Some of these proteins can function as oncogenes – such as cyclin D1, encoded by CCND1, which normally governs entry of the cell into S phase from G1. When overexpressed as a result of gene amplification or immunoglobulin H (IgH) translocation, the increased cyclin D1 promotes cycling and proliferation. See also Cell Cycle: Regulation by Cyclins

Inhibitors of apoptosis

In parallel with the mitogenic pathways are the pathways leading to cell death, which must be inhibited in order for malignant proliferation to proceed in exponential fashion. Inhibitors of apoptosis can thus function as oncogenes: the paradigm here is Bcl2, an antiapoptotic molecule bound to the mitochondrial membrane, serving to prevent caspase activation. Bcl2 is overexpressed in many lymphomas (Hesketh, 1997). See also Apoptosis: Molecular Mechanisms

Transcription factors

The endpoints of mitogenic, cell cycle and apoptotic signalling usually lie within the nucleus, where expression of proteins is altered at the level of transcription. Many pathways converge on transcription factors that promote or inhibit transcription of important genes. Not surprisingly, several of these transcription factors are themselves proto-oncogenes. MYC, for example, encodes an important transcription factor, regulating expression of many genes and being essential for cell cycle progression. Similarly, Fos and Jun proteins are activated by a number of mitogenic pathways. These proteins heterodimerize to each other and to other transcription factors, and thus may act as ‘AND’ gateways to protein expression, allowing transcription of important genes when several growth signals are present. See also Transcriptional Gene Regulation in Eukaryotes, and Gene Expression - External and Internal

Therapeutic Prospects

  1. Top of page
  2. Introduction
  3. Viral-induced Tumours
  4. Viral Oncogenes
  5. Cellular Oncogenes
  6. Normal Functions of Oncogenes
  7. Therapeutic Prospects
  8. Summary
  9. References
  10. Further Reading

If activation or deregulation of a proto-oncogene contributes to oncogenesis, then the corollary – that suppressing oncogene function may somehow stop cancer development – is an attractive hypothesis. Indeed, this has been the emphasis of many drug development strategies. There are several levels at which oncogene activity may be tackled: (1) at the level of transcription, where some level of control is re-exerted over oncogene expression, (2) at translation, where RNA message is inhibited, (3) through alteration of oncoprotein localization, stability, or function, (4) at the level of signal transduction pathways, which may be targeted upstream or downstream of the oncogene, and (5) at the level of immune response, which may be provoked into recognizing an abnormal, oncogenic protein. See also Cancer Therapy, the Future

Intervention in the EGFR signalling pathway

These levels of intervention are well exemplified by the EGFR–p21ras–Raf–MEK–ERK signalling pathway (Figure 2), which contains a number of proteins that may act as, or be replaced by, oncoproteins. Taking the levels of potential therapeutic manipulation described above, the first site for targeting is transcription. Here, preliminary success has been achieved using oligonucleotides that form triple helix structures at the site of promoters for EGF receptor family genes such as NEU (encoding erbB2), inhibiting the start of transcription. Other oligonucleotides are designed to act as decoys, binding to transcription factors in direct competition with the promotors. One level further, oligonucleotides antisense to messenger RNA (mRNA) have proven useful in preventing translation and promoting degradation of mRNA. Clinical trials are already underway using antisense to members of the EGF–p21ras–ERK pathway including RAS in lung cancer patients, and MYC in breast and prostate cancer (Gomez-Navarro et al., 1999). Despite problems of variable and unpredictable efficacy, and difficulties in delivering the oligonucleotides to their site of action, some anecdotal success is being reported. See also Small Regulatory RNAs in Bacteria, Prostate Cancer, and Nucleotides: Uncommon, Modified and Synthetic

Therapeutic targeting of the oncoproteins themselves may be mediated by antibodies – either extracellular antibodies directed, for example, to the erbB2 receptor (now an approved treatment for breast cancer), or intracellular antibodies (‘intrabodies’) like the anti-erbB2 single chain antibody (scFv), which has been shown to downregulate erbB2 expression (Gomez-Navarro et al., 1999). Activity may also be modified indirectly, using inhibitors of molecular chaperones such as Hsp90, which affects the folding and cellular localization of both erbB2 and Raf-1, ultimately leading to protein degradation. Similarly, clinical trials are currently underway to look at the effects of inhibitors of farnesyltransferase, which blocks p21ras farnesylation – a posttranscriptional modification essential for its membrane localization and function (Seckl, 2000). Finally, progress is being made using immunotherapeutic approaches to counter oncogenic members of the EGFR signalling pathways. Thus, T-cell responses have been generated to erbB2 and mutant p21ras, both in vitro and in vivo. See also Tumours: Immunotherapy, and Chaperones, Chaperonin and Heat-Shock Proteins

Bcr-Abl as a target for intervention

Another therapeutic oncogene target results from the Bcr-Abl juxtaposition in CML. This molecular translocation gives rise to a novel mRNA and a novel tyrosine kinase: both have been explored as sites for intervention. Antisense oligonucleotides to the hybrid transcript have had apparent effects in early clinical trials (Verfaillie et al., 1999), while a tyrosine kinase inhibitor, CGP 57148 (ST1 571), has similarly demonstrated impressive activity, at minimal toxicity, in phase I trials (Seckl, 2000).

Summary

  1. Top of page
  2. Introduction
  3. Viral-induced Tumours
  4. Viral Oncogenes
  5. Cellular Oncogenes
  6. Normal Functions of Oncogenes
  7. Therapeutic Prospects
  8. Summary
  9. References
  10. Further Reading

Oncogenes are genes that are directly involved in the development of malignancy, and may well be essential for this process. They are often derived from normal cellular genes, or proto-oncogenes, whose functions in cell proliferation, differentiation and survival have become deregulated. Oncogenes may be carried by viruses, or represent cellular genes that have been activated by viruses or by mutation. They usually operate in key cell signalling pathways, and have become important molecular targets for the development of novel anticancer agents, with some preliminary success. See also Cancer Treatment

Glossary
Cellular oncogene

A dominant gene present within a eukaryotic genome which has been activated by virus or mutation, and which can thus cause transformation and tumour formation.

Oncogene activation

The conversion from proto-oncogene to oncogene, mediated by viral insertion, viral transactivation or through gene mutation.

Oncoprotein

The protein product of a viral or cellular oncogene.

Proto-oncogene

A gene which encodes a protein required for normal cell survival and/or proliferation, which becomes a cellular oncogene when activated.

Transformation

An in vitro phenomenon whereby, through the action of oncogenes, primary cells adopt a phenotype of deregulated proliferation, demonstrating atypical morphology, loss of contact inhibition and colony formation.

Tumour suppressor

The converse of an oncogene; a recessive gene usually involved in preventing cell proliferation, which, when eliminated at both alleles, allows uncontrolled proliferation.

Viral oncogene

A gene carried by a retrovirus or DNA virus whose product causes cellular transformation in vitro, and/or contributes to tumour induction in vivo.

References

  1. Top of page
  2. Introduction
  3. Viral-induced Tumours
  4. Viral Oncogenes
  5. Cellular Oncogenes
  6. Normal Functions of Oncogenes
  7. Therapeutic Prospects
  8. Summary
  9. References
  10. Further Reading

Further Reading

  1. Top of page
  2. Introduction
  3. Viral-induced Tumours
  4. Viral Oncogenes
  5. Cellular Oncogenes
  6. Normal Functions of Oncogenes
  7. Therapeutic Prospects
  8. Summary
  9. References
  10. Further Reading