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Oncogenes
Secondary article
Article Contents
Amanda R Perry, Institute of Cancer Research, Sutton, Surrey, UK
. Introduction
Oncogenes are the activated forms of normal cellular genes whose protein products are
involved in key signalling pathways governing cell survival, proliferation and
differentiation. Through a variety of mechanisms, including viral infection and chemicalinduced mutation, these proteins become hyperactive or overexpressed and contribute to
the cell growth and behaviour typical of cancer cells.
. Viral-induced Tumours
. Viral Oncogenes
. Cellular Oncogenes
. Normal Functions of Oncogenes
. Therapeutic Prospects
. Summary
Introduction
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.
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
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.
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).
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
ENCYCLOPEDIA OF LIFE SCIENCES / & 2001 Macmillan Publishers Ltd, Nature Publishing Group / www.els.net
1
Oncogenes
Viral Oncogenes
Viral oncogene
Viral
RNA
Cellular Oncogenes
Radiation or chemical carcinogen
Reverse transcription
Point mutation in proto-oncogene
Integration into genomic DNA
Expression of viral oncoprotein
1. Retroviral transduction,
1. e.g. Rous sarcoma virus (src)
Viral RNA
Expression of mutant oncoprotein
5. Point mutation, e.g. RAS
LTR promotor
Reverse transcription
Amplification of proto-oncogene
Integration into genomic
DNA near proto-oncogene
Overexpression of
cellular oncoprotein
2. Retroviral insertion
Overexpression of
cellular oncoprotein
6. Gene amplification, e.g. EGFR
Expression of
viral oncoprotein
Viral DNA
Overexpression of cellular
oncoprotein
Translocation to
hyperactive promotor
Reciprocal translocation
(may not be expressed)
Viral
oncogene
Proto-oncogene
3. DNA viral expression
3. e.g. human papillomavirus – E6,7
Transactivating
viral oncoprotein
Overexpression
of cellular
oncoprotein
Promotor Protooncogene
7. Translocation to active
7. promotor/enhancer, e.g. IgH-MYC
Fusion oncoprotein
Translocation creating
fusion oncogene
Reciprocal fusion gene –
may not be expressed
Proto-oncogene
4. Viral transactivation, e.g. human
4. T cell leukaemia virus (Tax)I
8. Translocation to fusion partner,
8. e.g. BCR-ABL
Figure 1 Mechanisms of oncogene activation. LTR, long terminal repeat.
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.
Chronic retroviruses generally induce tumour formation
by the alternative mechanism of gene insertion, whereby
2
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.
ENCYCLOPEDIA OF LIFE SCIENCES / & 2001 Macmillan Publishers Ltd, Nature Publishing Group / www.els.net
Oncogenes
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.
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.
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.
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 illdefined, with no oncogenes being clearly identified.
Viral Oncogenes
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.
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.
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
ENCYCLOPEDIA OF LIFE SCIENCES / & 2001 Macmillan Publishers Ltd, Nature Publishing Group / www.els.net
3
Oncogenes
Table 1 Examples of retroviral oncogenes and their cellular homologues
Retrovirus
Viral oncogene
Cellular homologue
Abelson murine leukaemia virus
Avian erythroblastosis virus
FBJ murine osteosarcoma virus
Avian sarcoma virus-17
Avian myelocytomatosis virus
Murine sarcoma virus
Rous sarcoma virus
abl
erbA, erbB, ets
fos
jun
myc
H-ras, K-ras
src
ABL
ERBA, ERBB (EGFR), ETS
FOS
JUN
MYC
H-RAS, K-RAS
SRC
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.
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.
Cellular Oncogenes
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).
Activation by alterations of the coding
sequence
Point mutations and intragenic mutations arise as the
result of DNA damage caused by chemical agents, or
Table 2 Mechanisms of cellular oncogene activation
4
Malignancy
Oncogene
Mutation
Glioblastoma
Breast carcinoma
Breast carcinoma
Neuroblastoma
Pancreatic carcinoma
Colorectal carcinoma
Chronic myeloid leukaemia
Burkitt lymphoma
Follicular lymphoma
Mantle cell lymphoma
EGFR
ERB-B2
CCND1
ERB-B2
RAS
RAS
BCR-ABL
MYC
BCL2
CCND1
Amplification
Amplification
Amplification
Point mutation
Point mutation
Point mutation
Gene fusion
IgH juxtaposition
IgH juxtaposition
IgH juxtaposition
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Oncogenes
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).
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.
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 wellknown 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.
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.
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
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 proproliferative, 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.
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5
Oncogenes
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).
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.
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).
Membrane transducers
Two important categories of protein that transmit signals
from receptors to cytoplasmic molecules are the ‘nonreceptor 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.
Epidermal growth factor (EGF)
EGFR
Grb2
Raf
MEK
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.
p21ras
Sos1
MAPK
(ERK 1&2)
CYTOPLASM
NUCLEUS
MYC
FOS
JUN
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,
6
TRANSCRIPTION
Figure 2 The epidermal growth factor receptor (EGFR) signalling
pathway.
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Oncogenes
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.
Therapeutic Prospects
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.
EGF–p21ras –ERK pathway including RAS in lung cancer
patients, and MYC in breast and prostate cancer (GomezNavarro 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.
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, Tcell responses have been generated to erbB2 and mutant
p21ras, both in vitro and in vivo.
Bcr-Abl as a target for intervention
Another therapeutic oncogene target results from the BcrAbl 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).
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
Summary
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.
ENCYCLOPEDIA OF LIFE SCIENCES / & 2001 Macmillan Publishers Ltd, Nature Publishing Group / www.els.net
7
Oncogenes
References
Further Reading
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