Proto-oncogenes and Cancer
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Biochemistry Page
Introduction
Most,
if not all, cancer cells contain genetic damage that appears to be the
responsible event leading to tumorigenesis. The genetic damage present in a
parental tumorigenic cell is maintained (i.e. not correctable) such that it is
a heritable trait of all cells of subsequent generations. Genetic damage found
in cancer cells is of two types:
·
1. Dominant and the genes have been termed proto-oncogenes. The distinction between the terms proto-oncogene and
oncogene relates to the activity of the protein product of the gene. A
proto-oncogene is a gene whose protein product has the capacity to induce
cellular transformation given it sustains some genetic insult. An oncogene is a
gene that has sustained some genetic damage and, therefore, produces a protein
capable of cellular transformation.
The
process of activation of proto-oncogenes to oncogenes can include retroviral
transduction or retroviral integration (see below), point mutations, insertion
mutations, gene amplification, chromosomal translocation and/or protein-protein
interactions.
Proto-oncogenes
can be classified into many different groups based upon their normal function
within cells or based upon sequence homology to other known proteins. As
predicted, proto-oncogenes have been identified at all levels of the various
signal transduction cascades that control cell growth, proliferation and
differentiation. The list of proto-oncogenes identified to date is too lengthy
to include here, therefore, only those genes that have been highly
characterized are described. Proto-oncogenes that were originally identified as
resident in transforming retroviruses are designated as c-
indicative of the cellular origin as opposed to v- to signify original
identification in retroviruses.
·
2. Recessive and the genes variously termed tumor
suppressors, growth suppressors, recessive oncogenes or anti-oncogenes.
Given
the complexity of inducing and regulating cellular growth, proliferation and
differentiation, it was suspected for many years that genetic damage to genes
encoding growth factors, growth factor receptors and/or the proteins of the
various signal transduction cascades would lead to cellular transformation.
This suspicion has proven true with the identification of numerous genes, whose
products function in cellular signaling, that are involved in some way in the
genesis of the tumorigenic state. The majority of these proto-oncogenes were
identified by either of two means: as the transforming genes (oncogenes) of
transforming retroviruses or through transfection of DNA from tumor cell lines
into non-transformed cell lines and screening for resultant tumorigenesis.
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Viruses and Cancer
Tumor
cells also can arise by non-genetic means through the actions of specific tumor
viruses. Tumor viruses are of two distinct types. There are viruses with DNA
genomes (e.g. papilloma and adenoviruses) and those with RNA genomes (termed retroviruses).
RNA
tumor viruses are common in chickens, mice and cats but rare in humans. The
only currently known human retroviruses are the human T-cell leukemia viruses (HTLVs) and the related retrovirus, human immunodeficiency virus (HIV).
Retroviruses
can induce the transformed state within the cells they infect by two
mechanisms. Both of these mechanisms are related to the life cycle of these
viruses. When a retrovirus infects a cell its RNA genome is converted into DNA
by the viral encoded RNA-dependent DNA polymerase (reverse transcriptase). The DNA then integrates into the genome of the host
cell where it can remain being copied as the host genome is duplicated during
the process of cellular division. Contained within the sequences at the ends of
the retroviral genome are powerful transcriptional promoter sequences termed long terminal repeats (LTRs). The LTRs promote the transcription of the viral DNA
leading to the production of new virus particles.
At
some frequency the integration process leads to rearrangement of the viral
genome and the consequent incorporation of a portion of the host genome into
the viral genome. This process is termed transduction. Occasionally this
transduction process leads to the virus acquiring a gene from the host that is
normally involved in cellular growth control. Because of the alteration of the
host gene during the transduction process as well as the gene being transcribed
at a higher rate due to its association with the retroviral LTRs the transduced
gene confers a growth advantage to the infected cell. The end result of this
process is unrestricted cellular proliferation leading to tumorigenesis. The
transduced genes are termed oncogenes. The normal cellular gene in its
unmodified, non-transduced form is termed a proto-oncogene since it has the
capacity to transform cells if altered in some way or expressed in an
uncontrolled manner. Numerous oncogenes have been discovered in the genomes of
transforming retroviruses.
The
second mechanism by which retroviruses can transform cells relates to the
powerful transcription promoting effect of the LTRs. When a retrovirus genome
integrates into a host genome it does so randomly. At some frequency this
integration process leads to the placement of the LTRs close to a gene that
encodes a growth regulating protein. If the protein is expressed at an
abnormally elevated level it can result in cellular transformation. This is
termed retroviral integration induced transformation. It has recently been
shown that HIV induces certain forms of cancers in infected individuals by this
integration induced transformation process.
Cellular
transformation by DNA tumor viruses, in most cases, has been shown to be the
result of protein-protein interaction. Proteins encoded by the DNA tumor
viruses, termed tumor
antigens or T antigens, can interact
with cellular proteins. This interaction effectively sequesters the cellular
proteins away from their normal functional locations within the cell. The
predominant types of proteins that are sequestered by viral T antigens have
been shown to be of the tumor suppressor type. It is the loss of their normal
suppressor functions that results in cellular transformation.
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Classifications of Proto-Oncogenes
Although
there are numerous examples of each classification of proto-oncogene, the lists
here are by no means exhaustive. New genes with tumor causing capabilitites are
being isolated continuously.
Growth Factors
The
c-Sis gene (the v-sis gene is the oncogene in simian sarcoma virus) encodes the
PDGF B chain. The v-sis gene was the first oncogene to be identified as having
homology to a known cellular gene. The int-2 gene (named for the fact that it
is a common site of integration of mouse mammary tumor virus) encodes an
FGF-related growth factor. The KGF (also called Hst) gene also encodes an
FGF-related growth factor and was identified in gastric carcinoma and Kaposi's
sarcoma cells.
Receptor Tyrosine Kinases
The
c-Fms (fims)gene encodes the colony stimulating factor-1 (CSF-1)
receptor. and was first identified as a retroviral oncogene. The Flg (flag)
gene (named because it has homology to the Fms [fims] gene, hence fms-like
gene) encodes a form of the FGF receptor. The Neu (new)
gene was identified as an EGF receptor-related gene in an
ethylnitrosourea-induced neuroblastoma. The conversion of
proto-oncogenic to oncogenic Neu requires only a single amino acid change in
the transmembrane domain. The Trk (track) genes encodes the NGF
receptor-like proteins. The first Trk gene was found in a pancreatic cancer.
Subsequently, two additional Trk-related genes were identified. These three are
now identified as TrkA, TrkB and TrkC. The Met gene encodes the hepatocyte
growth factor(HGF)/scatter factor (SF) receptor. The c-Kit gene encodes the
mast cell growth factor receptor.
Membrane Associated Non-Receptor Tyrosine Kinases
The
v-src gene was the first identified oncogene. The c-Src gene is the archetypal
protein tyrosine kinase. The Lck gene was isolated from a T cell tumor line (LYSTRA
cell kinase) and has been shown
to be associated with the CD4 and CD8 antigens of T cells.
G-Protein Coupled Receptors
The
Mas gene was identified in a mammary carcinoma and has been shown to be the
angiotensin receptor.
Membrane Associated G-Proteins
There
are three different homologs of the c-Ras gene, each of which was identified in
a different type of tumor cell. The Ras gene is one of the most frequently
disrupted genes in colorectal carcinomas.
Serine/Threonine Kinases
The
Raf gene is involved in the signaling pathway of most RTKs. It is likely
responsible for threonine phosphorylation of MAP kinase following receptor
activation.
Nuclear DNA-Binding/Transcription Factors
The
Myc gene was originally identified in the avian myelocytomatosis
virus. A disrupted human c-Myc gene has been found to be involved in numerous
hematopoietic neoplasias. Disruption of c-Myc has been shown to be the result
of retroviral integration and transduction as well as chromosomal
rearrangements. The Fos gene was identified in the feline
osteosarcoma virus. The protein interacts with a second
proto-oncogenic protein, Jun to form a transcriptional regulatory complex. The
p53 gene was originally identified as a major nuclear antigen in transformed
cells. The p53 gene is the single most identified mutant protein in human
tumors. Mutant forms of the p53 protein interfere with cell growth suppressor
effects of wild-type p53 indicating that the p53 gene product is actually a tumor suppressor.
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Hereditary Cancer Syndromes
|
Syndrome |
Cloned Gene |
Function |
Chromosomal Location |
Tumor Types |
|
P53 |
cell cycle regulation, apoptosis |
17p13 |
brain tumors, sarcomas, leukemia, breast cancer |
|
|
RB1 |
cell cycle regulation |
13q14 |
retinoblastoma, osteogenic sarcoma |
|
|
WT1 |
transcriptional regulation |
11p13 |
pediatric kidney cancer |
|
|
NF1 |
catalysis of RAS inactivation |
17q11.2 |
neurofibromas, sarcomas, gliomas |
|
|
Neurofibromatosis Type 2 |
NF2 |
linkage of cell membrane to cytoskeleton |
22q12.2 |
Schwann cell tumors, astrocytomas, meningiomas, ependynomas |
|
APC |
signaling through adhesion molecules to nucleus |
5q21 |
colon cancer |
|
|
Tuberous sclerosis 1 |
TSC1 |
|
9q34 |
facial angiofibromas |
|
Tuberous sclerosis 2 |
TSC2 |
GTPase activation |
16 |
benign growths (hamartomas) in many tissues, astrocytomas, rhabdomyosarcomas |
|
Deleted in Pancreatic Carcinoma 4 |
DPC4 |
regulation of TGF-b/BMP signal transduction |
18q21.1 |
pancreatic carcinoma, colon cancer |
|
Familial Breast Cancer |
BRCA1 |
repair of double strand breaks by association with Rad51 protein |
17q21 |
breast and ovarian cancer |
|
Familial Breast Cancer |
BRCA2 |
similar to BRCA1? |
13q12.3 |
breast and ovarian cancer |
|
Hereditary Nonpolyposis Colorectal Cancer |
MSH2 |
DNA mismatch repair |
2p16 |
colorectal cancer |
|
Hereditary Nonpolyposis Colorectal Cancer |
MLH1 |
DNA mismatch repair |
3p21 |
colorectal cancer |
|
von Hippel-Lindau Syndrome |
VHL |
regulation of transcription elongation |
3p26-p25 |
renal cancers, hemangioblastomas, pheochromocytoma |
|
Familial Melanoma |
CDKN2A |
cell-cycle regulation |
9p21 |
melanoma, pancreatic cancer, others |
|
Gorlin Syndrome: |
PTCH |
transmembrane receptor for hedgehog signaling protein |
9q22.3 |
basal cell skin cancer |
|
Multiple Endocrine Neoplasia Type 1 |
MEN1 |
unknown |
11q13 |
parathyroid and pituitary adenomas, islet cell tumors, carcinoid |
|
Multiple Endocrine Neoplasia Type 2 |
RET, MEN2 |
transmembrane receptor tyrosine kinase for glial-derived neurotrophic factor (GDNF) |
10q11.2 |
medullary thyroid cancer, type 2A pheochromocytoma, mucosal hartoma |
|
Beckwith-Wiedmann Syndrome |
p57, KIP2 |
cell cycle regulator |
11p15.5 |
Wilms tumor, adrenocortical cancer, hepatoblastoma |
|
Hereditary papillary renal cancer (HPRC) |
MET |
transmembrane receptor for hepatocyte growth factor (HGF) |
7q31 |
renal papillary cancer |
|
Cowden disease |
PTEN |
dual-specificity phosphatase, similar to tensin |
10q23.3 |
brest cancer, thyroid cancer, intestinal hamartomous polyps |
|
Hereditary prostate cancer (HPC) |
unknown |
unknown |
1q24-q25 |
prostate cancer |
|
Ataxia telangiectasia (AT) |
ATM |
DNA repair |
11q22.3 |
lymphoma, cerebellar ataxia, immunodeficiency |
|
Bloom syndrome |
BLM |
DNA helicase? |
15q26.1 |
solid tumors, immunodeficiency |
|
Xeroderma pigmentosum (XP) |
several complimentation groups: XPA, XPC, XPD, XPE, XPF |
DNA repair helicases, nucleotide excision repair |
XPA = 9q22.3 |
skin cancer |
|
Fanconi's anemia |
FACA, FACC |
DNA repair? |
FACA=16q24.3 |
acute myeloid leukemia (AML), pancytopenia |
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Last modified: Wednesday, 07-Jun-00 12:58:57