Oncogenes (tumor-causing genes) were originally
identified in RNA tumor viruses (retroviruses)
as genes (v-onc) that could transform
cells into an altered state of control of cell proliferation,
often resulting in a tumor, mainly in
chicken, mice, and rats. More than 20 different
viral oncogenes are known to have a counterpart
in normal cells (c-onc), called proto-oncogenes
or cellular oncogenes. These cellular
genes are highly conserved in evolution because
they have important functions in all
eukaryotic cells. They encode proteins that are
required at defined sites throughout the cell
where they regulate the ordered progression
through the cell cycle, cell division, and differentiation.
Sunday, April 12, 2009
Cellular and viral oncogenes
A typical retrovirus contains an RNA genome
that codes for three genes or groups of genes:
gag (group-specific antigen), pol (polymerase),
and env (coat protein, envelope). As with all
genes of higher organisms, a cellular oncogene
(c-onc) consists of exons and introns with defined
structure and sequence, as in the gene src
(the name is derived from sarcoma, a tumor
that is induced by a change in this gene). The
virus may contain parts of the cellular oncogene
(c-scr). This is designated viral oncogene (v-src)
(Rous sarcoma virus). In chickens, it induces a
malignant tumor (a sarcoma), first observed by
Peyton Rous in 1911. Since many cellular oncogenes
are also known in an altered, viral form, it
is assumed that the viruses have integrated
parts of the respective cellular oncogenes into
their own genomes.
that codes for three genes or groups of genes:
gag (group-specific antigen), pol (polymerase),
and env (coat protein, envelope). As with all
genes of higher organisms, a cellular oncogene
(c-onc) consists of exons and introns with defined
structure and sequence, as in the gene src
(the name is derived from sarcoma, a tumor
that is induced by a change in this gene). The
virus may contain parts of the cellular oncogene
(c-scr). This is designated viral oncogene (v-src)
(Rous sarcoma virus). In chickens, it induces a
malignant tumor (a sarcoma), first observed by
Peyton Rous in 1911. Since many cellular oncogenes
are also known in an altered, viral form, it
is assumed that the viruses have integrated
parts of the respective cellular oncogenes into
their own genomes.
Virus-induced tumors
Virus-induced tumors are known especially in
chickens, rodents, and cats. In man, they do not
play a general role in the induction of tumors.
Important exceptions are papilloma virus-induced
carcinoma of the cervix and carcinoma of
the liver secondary to hepatitis virus infection.
chickens, rodents, and cats. In man, they do not
play a general role in the induction of tumors.
Important exceptions are papilloma virus-induced
carcinoma of the cervix and carcinoma of
the liver secondary to hepatitis virus infection.
Mechanisms of oncogene activation
A cellular oncogene controls cell division. It
controls the time and location of the orderly
proliferation of cells and tissues (normal
growth). Genetic changes can lead to disorders
of the regulation of cell divison, increased proliferation
of cells, and formation of a tumor. This
can be traced back to relatively few mechanisms.
A point mutation in a critical region of
the gene can lead to disturbances in the regulation
of cell division. Examples are mutations in
codon 12 or 63 or the H-ras gene.
An inactive cellular oncogene may become activated
when it is moved by chromosomal translocation
to the vicinity of an active gene. In
Burkitt lymphoma, an inactive gene is moved to
the region of an active gene for the H or L chain
of an immunoglobulin. In other cases, the
breakpoint of the chromosome translocation
may lie within a cellular oncogene and thereby
affect its expression. An example is the
Philadelphia translocation (see p. 332). Multiplication
(amplification) of a gene is a futher
mechanism that can lead to altered (usually increased)
expression.
controls the time and location of the orderly
proliferation of cells and tissues (normal
growth). Genetic changes can lead to disorders
of the regulation of cell divison, increased proliferation
of cells, and formation of a tumor. This
can be traced back to relatively few mechanisms.
A point mutation in a critical region of
the gene can lead to disturbances in the regulation
of cell division. Examples are mutations in
codon 12 or 63 or the H-ras gene.
An inactive cellular oncogene may become activated
when it is moved by chromosomal translocation
to the vicinity of an active gene. In
Burkitt lymphoma, an inactive gene is moved to
the region of an active gene for the H or L chain
of an immunoglobulin. In other cases, the
breakpoint of the chromosome translocation
may lie within a cellular oncogene and thereby
affect its expression. An example is the
Philadelphia translocation (see p. 332). Multiplication
(amplification) of a gene is a futher
mechanism that can lead to altered (usually increased)
expression.
Examples of cellular oncogenes and their proteins
The table shows examples of the about 60
known cellular oncogenes, their basic functions,
a fewtumors induced inman by mutation
of the cellular oncogene (c-onc), and tumors induced
in vertebrates by the homologous viral
onogene (v-onc).
known cellular oncogenes, their basic functions,
a fewtumors induced inman by mutation
of the cellular oncogene (c-onc), and tumors induced
in vertebrates by the homologous viral
onogene (v-onc).
The p53 Protein, a Guardian of the Genome
The p53 protein (named after its molecular
weight of 53 kD), a nuclear phosphoprotein, is
indispensable for genomic integrity and cell
cycle control. It binds to specific DNA sequences
and regulates the expression of different regulatory
genes involved in growth. It interacts
with other proteins in response to DNA damage
and mediates apoptosis (cell death) of the cell
when the damage is beyond repair. Its basic
function is to control entry of the cell into the S
phase (see cell cycle control, p. 112). Somatic
mutations in the p53 gene occur in about half of
all tumors. Germline mutations lead to a familial
form of multiple different cancers
weight of 53 kD), a nuclear phosphoprotein, is
indispensable for genomic integrity and cell
cycle control. It binds to specific DNA sequences
and regulates the expression of different regulatory
genes involved in growth. It interacts
with other proteins in response to DNA damage
and mediates apoptosis (cell death) of the cell
when the damage is beyond repair. Its basic
function is to control entry of the cell into the S
phase (see cell cycle control, p. 112). Somatic
mutations in the p53 gene occur in about half of
all tumors. Germline mutations lead to a familial
form of multiple different cancers
The human p53 protein
The active form of the human p53 protein is a
tetramer of four identical subunits. Each subunit
has 393 amino acids and five highly conserved
regions, I–V. Region I is part of the transcription-
activation domain; regions II–V
belong to sequence-specific DNA-binding
domains. The carboxyl end beyond amino acid
300 consists of a nonspecific DNA interaction
domain and the tetramerization domain. Proteins
encoded by DNA tumor viruses bind to
p53 and inhibit its activity.Mutations in the p53
gene on human chromosome 17 at p13 (spanning
20 kb of DNA and yielding a 2.8 kb mRNA
transcript from 11 exons) have the greatest effect
when they occur in the conserved regions
II–V in codons 129–146 (exon 4), 171–179
(exon 5), 234–260 (exon 7), and 270–287 (exon
8). Particularly vulnerable are the conserved
amino acids arginine (R) in positions 175, 248,
249, 273, and 282 and glycine (G) in position
245. Mutations occur mainly as missense, resulting
from base-pair substitutions, but some
are insertions and deletions and exert a dominant
negative effect. Knockout mice develop
normally, but develop tumors at a high rate. Activated
benzopyrene induces mutations at codons
175, 248, and 275 in cultured bronchial
epithelial cells.
tetramer of four identical subunits. Each subunit
has 393 amino acids and five highly conserved
regions, I–V. Region I is part of the transcription-
activation domain; regions II–V
belong to sequence-specific DNA-binding
domains. The carboxyl end beyond amino acid
300 consists of a nonspecific DNA interaction
domain and the tetramerization domain. Proteins
encoded by DNA tumor viruses bind to
p53 and inhibit its activity.Mutations in the p53
gene on human chromosome 17 at p13 (spanning
20 kb of DNA and yielding a 2.8 kb mRNA
transcript from 11 exons) have the greatest effect
when they occur in the conserved regions
II–V in codons 129–146 (exon 4), 171–179
(exon 5), 234–260 (exon 7), and 270–287 (exon
8). Particularly vulnerable are the conserved
amino acids arginine (R) in positions 175, 248,
249, 273, and 282 and glycine (G) in position
245. Mutations occur mainly as missense, resulting
from base-pair substitutions, but some
are insertions and deletions and exert a dominant
negative effect. Knockout mice develop
normally, but develop tumors at a high rate. Activated
benzopyrene induces mutations at codons
175, 248, and 275 in cultured bronchial
epithelial cells.
Germline mutations of p53
In 1969, Li and Fraumeni identified families in
whom other members were affected with
diverse types of tumors, mainly soft-tissue sarcomas,
early-onset breast cancer, brain cancers,
cancer of the bone (osteosarcoma) and bone
marrow(leukemias), and carcinoma of the lung,
pancreas, and adrenal cortex. Similar observations
had been reported as “cancer family syndrome”
by Lynch. This autosomal dominant
cancer syndrome is called the Li–Fraumeni
syndrome (McKusick 114480). In the pedigree
shown in panel 1, four individuals (II-2, II-3, III-
1, III-2) are affected by different types of
tumors. A mutation in codon 248 of the p53
gene (CGG arginine, to TGG, tryptophan) is
present in these patients. The mutation is also
present in individuals I-1 and III-5. This places
these individuals at increased risk for one of the
types of cancer mentioned above and shown in
panel 2. In contrast, absence of the mutation in
individuals III-3 and III-4 indicates that they do
not have an increased risk of cancer (Data of
D. Malkin). A subset of patients with Li–Fraumeni
syndrome does not show p53 mutations.
whom other members were affected with
diverse types of tumors, mainly soft-tissue sarcomas,
early-onset breast cancer, brain cancers,
cancer of the bone (osteosarcoma) and bone
marrow(leukemias), and carcinoma of the lung,
pancreas, and adrenal cortex. Similar observations
had been reported as “cancer family syndrome”
by Lynch. This autosomal dominant
cancer syndrome is called the Li–Fraumeni
syndrome (McKusick 114480). In the pedigree
shown in panel 1, four individuals (II-2, II-3, III-
1, III-2) are affected by different types of
tumors. A mutation in codon 248 of the p53
gene (CGG arginine, to TGG, tryptophan) is
present in these patients. The mutation is also
present in individuals I-1 and III-5. This places
these individuals at increased risk for one of the
types of cancer mentioned above and shown in
panel 2. In contrast, absence of the mutation in
individuals III-3 and III-4 indicates that they do
not have an increased risk of cancer (Data of
D. Malkin). A subset of patients with Li–Fraumeni
syndrome does not show p53 mutations.
Model of function of the p53 gene
Normally, the p53 gene is inactive (1). p53 plays
an important role in regulating growth in damaged
cells (2). DNA damage in cells leads to increased
expression of p53 and interruption of
the cell cycle in G1. If DNA repair is successful,
the cell can continue its cycle. If repair is not
successful, the cell dies (cell death, apoptosis).
Damaged cells with p53 protein that is mutant
are not arrested in G1.
an important role in regulating growth in damaged
cells (2). DNA damage in cells leads to increased
expression of p53 and interruption of
the cell cycle in G1. If DNA repair is successful,
the cell can continue its cycle. If repair is not
successful, the cell dies (cell death, apoptosis).
Damaged cells with p53 protein that is mutant
are not arrested in G1.
Neurofibromatosis 1 and 2
The neurofibromatoses are clinically and
genetically different autosomal dominant
hereditary diseases that predispose to benign
and malignant tumors of the nervous system.
Numerous different forms are known. The most
important are neurofibromatosis 1 (NF1, von
Recklinghausen disease, MIM 162200) and neurofibromatosis
2 (NF2, MIM 101000).
genetically different autosomal dominant
hereditary diseases that predispose to benign
and malignant tumors of the nervous system.
Numerous different forms are known. The most
important are neurofibromatosis 1 (NF1, von
Recklinghausen disease, MIM 162200) and neurofibromatosis
2 (NF2, MIM 101000).
The main signs of NF1
NF1 is very variable. Lisch nodules of the iris (1)
in more than 90% of patients, café-au-lait spots
(2) (more than five spots of more than 2 cm
diameter are considered diagnostic) in more
than 95%, and multiple neurofibromas (3) in
more than 90% of patients are the most important
signs.
in more than 90% of patients, café-au-lait spots
(2) (more than five spots of more than 2 cm
diameter are considered diagnostic) in more
than 95%, and multiple neurofibromas (3) in
more than 90% of patients are the most important
signs.
Neurofibromatosis gene NF1 on human chromosome 17 at q11.2
The localization of the NF1 gene revealed the
gene on a 600 kb NruI restriction fragment. A
CpG island (CpG-1) and two translocation
breakpoints at t(17;22) and t(1;17) served as
important anchor points for gene identification.
The NF1 gene has 79 exons, which span about
335 kb of genomic DNA. Three unrelated genes,
OMGP, EVI2B, and EVI2A, are embedded within
the NF1 gene in intron 35 on the opposite DNA
strand. Mutation analysis of the NF1 gene shows
deletions, insertions, base substitutions, and
splice mutations leading to truncated and presumably
nonfunctional gene products. Currently
mutations are found in about 60–70% of
patients.
gene on a 600 kb NruI restriction fragment. A
CpG island (CpG-1) and two translocation
breakpoints at t(17;22) and t(1;17) served as
important anchor points for gene identification.
The NF1 gene has 79 exons, which span about
335 kb of genomic DNA. Three unrelated genes,
OMGP, EVI2B, and EVI2A, are embedded within
the NF1 gene in intron 35 on the opposite DNA
strand. Mutation analysis of the NF1 gene shows
deletions, insertions, base substitutions, and
splice mutations leading to truncated and presumably
nonfunctional gene products. Currently
mutations are found in about 60–70% of
patients.
NF1 gene product (neurofibromin)
The NF1 gene encodes a gene product with 2810
amino acids, called neurofibromin. Between
amino acids 840 and 1200, this large protein
contains a domain that corresponds to a
GTPase-activating protein. The homology includes
a gene product in yeast (S. cerevisiae),
IRA1 (inhibitor of ras mutants). Mutations at
the NF1 locus interrupt a signal pathway to the
ras genes.
amino acids, called neurofibromin. Between
amino acids 840 and 1200, this large protein
contains a domain that corresponds to a
GTPase-activating protein. The homology includes
a gene product in yeast (S. cerevisiae),
IRA1 (inhibitor of ras mutants). Mutations at
the NF1 locus interrupt a signal pathway to the
ras genes.
Neurofibromatosis gene NF2 on human chromosome 22 at q12.1
The NF2 genewas identified in 1993 by Rouleau
et al. and Trofatter et al. within a cosmid contig
contained in YAC clones (yeast artificial chromosomes).
Two deletions observed in unrelated
patients aided in finding the almost 100
kb gene with 17 exons. Mutations can be detected
in more than 50% of patients (large deletions
including the entire gene or several exons
and small deletions are frequent). The gene
product, called schwannomin, is related to a
family of cytoskeleton-membrane proteins
(erythrocyte protein 4.1, see p. 374, and the ERM
family ezrin, radixin, and moesin) and a family
of protein tyrosine phosphatases. The basic
function of these proteins is to maintain cellular
integrity.
et al. and Trofatter et al. within a cosmid contig
contained in YAC clones (yeast artificial chromosomes).
Two deletions observed in unrelated
patients aided in finding the almost 100
kb gene with 17 exons. Mutations can be detected
in more than 50% of patients (large deletions
including the entire gene or several exons
and small deletions are frequent). The gene
product, called schwannomin, is related to a
family of cytoskeleton-membrane proteins
(erythrocyte protein 4.1, see p. 374, and the ERM
family ezrin, radixin, and moesin) and a family
of protein tyrosine phosphatases. The basic
function of these proteins is to maintain cellular
integrity.
APC Gene in Familial Polyposis Coli
Cancer of the colon and rectum is the second
leading cause of death from cancer. About 5% of
the population can be expected to develop
colorectal cancer. Most colorectal tumors arise
from a series of somatic mutations in several
genes.
leading cause of death from cancer. About 5% of
the population can be expected to develop
colorectal cancer. Most colorectal tumors arise
from a series of somatic mutations in several
genes.
Polyposis coli and colon carcinoma
Familial polyposis (FAP) is an autosomal dominant
hereditary disease. In late childhood and
early adulthood, up to 1000 and more polyps
develop in the mucous membrane of the large
intestine (colon) (1). Each polyp can develop
into a carcinoma (2). In about 85% of affected
persons, small hypertrophic areas that do not
affect vision are present in the retina (3).
Hereditary non-polyposis colorectal cancer
hereditary disease. In late childhood and
early adulthood, up to 1000 and more polyps
develop in the mucous membrane of the large
intestine (colon) (1). Each polyp can develop
into a carcinoma (2). In about 85% of affected
persons, small hypertrophic areas that do not
affect vision are present in the retina (3).
Hereditary non-polyposis colorectal cancer
Mutations at different gene loci in polyposis coli and carcinoma of the colon
At least six gene loci are involved in the
development of carcinoma of the colon associated
with polyposis coli. Somatic mutations
may occur in two recessive oncogenes (Ras
genes KRAS1 and KRAS2) and in four dominant
tumor suppressor genes. Most forms of carcinoma
of the colon are not associated with polyposis
coli.
development of carcinoma of the colon associated
with polyposis coli. Somatic mutations
may occur in two recessive oncogenes (Ras
genes KRAS1 and KRAS2) and in four dominant
tumor suppressor genes. Most forms of carcinoma
of the colon are not associated with polyposis
coli.
The APC gene and distributions of mutations
The APC gene (adenoma polyposis coli) consists
of 8538 bp in 15 exons encoding a 2843-aminoacid
protein (not 8535 bp and 2844 amino acids
as shown in C). Exon 15 is very large, 6579 base
pairs. Over 95% of mutations result in a nonfunctional
truncated protein due to nonsense
mutations (40%), deletions (41%), insertions
(12%), and splice site mutations (7%).
of 8538 bp in 15 exons encoding a 2843-aminoacid
protein (not 8535 bp and 2844 amino acids
as shown in C). Exon 15 is very large, 6579 base
pairs. Over 95% of mutations result in a nonfunctional
truncated protein due to nonsense
mutations (40%), deletions (41%), insertions
(12%), and splice site mutations (7%).
Indirect DNA diagnosis in FAP
Linked DNAmarkers (RFLPs) near the APC locus
(1) can be used for indirect DNA diagnosis. The
alleles of three flanking marker pairs (K,k and
E,e on the centromere side and A,a on the distal
side) form the haplotypes, e.g., e–K–a and
E–k–a in individual I-1 in the pedigree (2). The
mutation-carrying haplotype must be e–K–a.
Since individual III-2 has inherited this haplotype,
he is at risk for the disease, whereas individual
III-1 is not.
(1) can be used for indirect DNA diagnosis. The
alleles of three flanking marker pairs (K,k and
E,e on the centromere side and A,a on the distal
side) form the haplotypes, e.g., e–K–a and
E–k–a in individual I-1 in the pedigree (2). The
mutation-carrying haplotype must be e–K–a.
Since individual III-2 has inherited this haplotype,
he is at risk for the disease, whereas individual
III-1 is not.
Several mutations in the production of colon carcinoma
Tumor formation goes through several stages. It
starts with a somatic or germinal mutation in
the APC gene. After loss of the other allele (LOH),
an adenoma develops with less-differentiated
cells and polyp formation. Mutations in other
genes lead to malignant transformation and
eventually to tumor development.
starts with a somatic or germinal mutation in
the APC gene. After loss of the other allele (LOH),
an adenoma develops with less-differentiated
cells and polyp formation. Mutations in other
genes lead to malignant transformation and
eventually to tumor development.
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