Oncogenes

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Chapter 28

• Oncogenes
• and
• cancer

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28.1 Introduction28.2 Transforming viruses carry
oncogenes28.3 Early genes of DNA transforming
viruses have multifunction oncogenes28.4
Retroviruses activate or incorporate cellular
genes28.5 Retroviral oncogenes have cellular
counterparts28.6 Ras oncogenes can be detected
in a transfection assay28.7 Ras proto-oncogenes
can be activated by mutation at specific
positions28.8 Nondefective retroviruses activate
proto-oncogenes28.9 Proto-oncogenes can be
activated by translocation28.10 The Philadelphia
translocation generates a new oncogene28.11
Oncogenes code for components of signal
transduction cascades28.12 Growth factor
receptor kinases can be mutated to
oncogenes28.13 Src is the prototype for the
proto-oncogenic cytoplasmic tyrosine
kinases 28.14 Oncoproteins may regulate gene
expression28.15 RB is a tumor suppressor that
controls the cell cycle28.16 Tumor suppressor
p53 suppresses growth or triggers apoptosis28.17
p53 is a DNA-binding protein28.18 p53 is
controlled by other tumor suppressors and
oncogenes28.19 Immortalization and
transformation are independent28.20 Telomere
shortening causes cell mortality
3
Anchorage dependence describes the need of normal
eukaryotic cells for a surface to attach to in
order to grow in culture.Aneuploid chromosome
constitution differs from the usual diploid
constitution by loss or duplication of
chromosomes or chromosomal segments.Metastasis
describes the ability of tumor cells to leave
their site of origin and migrate to other
locations in the body, where a new colony is
established.Monolayer describes the growth of
eukaryotic cells in culture as a layer only one
cell deep.Oncogenes are genes whose products
have the ability to transform eukaryotic cells so
that they grow in a manner analogous to tumor
cells. Oncogenes carried by retroviruses have
names of the form v-onc.
28.1 Introduction
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Primary cells are eukaryotic cells taken into
culture directly from the animal.Proto-oncogenes
are the normal counterparts in the eukaryotic
genome to the oncogenes carried by some
retroviruses. They are given names of the form
c-onc .Serum dependence describes the need of
eukaryotic cells for factors contained in serum
in order to grow in culture.Transformation of
bacteria describes the acquisition of new genetic
markers by incorporation of added DNA.
28.1 Introduction
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Figure 28.1 Three types of properties distinguish
a cancer cell from a normal cell. Sequential
changes in cultured cells can be correlated with
changes in tumorigenicity.
28.1 Introduction
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Figure 28.1 Three types of properties distinguish
a cancer cell from a normal cell. Sequential
changes in cultured cells can be correlated with
changes in tumorigenicity.
28.1 Introduction
7
Figure 28.2 Normal fibroblasts grow as a layer of
flat, spread-out cells, whereas transformed
fibroblasts are rounded up and grow in cell
masses. The cultures on the left contain normal
cells, those on the right contain transformed
cells. The top views are by conventional
microscopy, the bottom by scanning electron
microscopy. Photographs kindly provided by
Hidesaburo Hanafusa and J. Michael Bishop.
28.1 Introduction
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Figure 28.3 Transforming viruses may carry
oncogenes.
28.2 Transforming viruses carry oncogenes
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Figure 28.4 Permissive cells are productively
infected by a DNA tumor virus that enters the
lytic cycle, while nonpermissive cells are
transformed to change their phenotype.
28.2 Transforming viruses carry oncogenes
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Figure 28.5 Cells transformed by polyomaviruses
or adenoviruses have viral sequences that include
the early region integrated into the cellular
genome. Sites of integration are random.
28.2 Transforming viruses carry oncogenes
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Figure 28.6 Retroviruses transfer genetic
information horizontally by infecting new hosts
information is inherited vertically if a virus
integrates in the genome of the germline.
28.2 Transforming viruses carry oncogenes
12
Figure 16.2 The retroviral life cycle proceeds by
reverse transcribing the RNA genome into duplex
DNA, which is inserted into the host genome, in
order to be transcribed into RNA.
28.2 Transforming viruses carry oncogenes
13
Figure 28.7 A transforming retrovirus carries a
copy of a cellular sequence in place of some of
its own gene(s).
28.2 Transforming viruses carry oncogenes
14
Proto-oncogenes are the normal counterparts in
the eukaryotic genome to the oncogenes carried by
some retroviruses. They are given names of the
form c-onc .
28.3 Retroviral oncogenes have cellular
counterparts
15
Figure 28.8 Each transforming retrovirus carries
an oncogene derived from a cellular gene. Viruses
have names and abbreviations reflecting the
history of their isolation and the types of tumor
they cause. This list shows some representative
examples of the retroviral oncogenes
28.3 Retroviral oncogenes have cellular
counterparts
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Figure 28.8 Each transforming retrovirus carries
an oncogene derived from a cellular gene. Viruses
have names and abbreviations reflecting the
history of their isolation and the types of tumor
they cause. This list shows some representative
examples of the retroviral oncogenes
28.3 Retroviral oncogenes have cellular
counterparts
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Figure 28.8 Each transforming retrovirus carries
an oncogene derived from a cellular gene. Viruses
have names and abbreviations reflecting the
history of their isolation and the types of tumor
they cause. This list shows some representative
examples of the retroviral oncogenes
28.3 Retroviral oncogenes have cellular
counterparts
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Figure 28.9 The transfection assay allows (some)
oncogenes to be isolated directly by assaying DNA
of tumor cells for the ability to transform
normal cells into tumorigenic cells.
28.4 Ras proto-oncogenes can be activated by
mutation
19
Figure 28.9 The transfection assay allows (some)
oncogenes to be isolated directly by assaying DNA
of tumor cells for the ability to transform
normal cells into tumorigenic cells.
28.4 Ras proto-oncogenes can be activated by
mutation
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Figure 28.8 Each transforming retrovirus carries
an oncogene derived from a cellular gene. Viruses
have names and abbreviations reflecting the
history of their isolation and the types of tumor
they cause. This list shows some representative
examples of the retroviral oncogenes
28.3 Retroviral oncogenes have cellular
counterparts
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Figure 28.10 Pathways that rely on Ras could
function by controlling either GNRF or GAP.
Oncogenic Ras mutants are refractory to control,
because Ras remains in the active form.
28.4 Ras proto-oncogenes can be activated by
mutation
22
Reciprocal translocation exchanges part of one
chromosome with part of another chromosome.
28.5 Insertion, translocation, or amplification
may activate proto-oncogenes
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Figure 17.29 Amplified copies of the dhfr gene
produce a homogeneously staining region (HSR) in
the chromosome. Photograph kindly provided by
Robert Schimke.
28.5 Insertion, translocation, or amplification
may activate proto-oncogenes
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Figure 17.30 Amplified extrachromosomal dhfr
genes take the form of double-minute chromosomes,
as seen in the form of the small white dots.
Photograph kindly provided by Robert Schimke.
28.5 Insertion, translocation, or amplification
may activate proto-oncogenes
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Figure 28.11 Insertions of ALV at the c-myc locus
occur at various positions, and activate the gene
in different ways.
28.5 Insertion, translocation, or amplification
may activate proto-oncogenes
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Figure 28.12 A chromosomal translocation is a
reciprocal event that exchanges parts of two
chromosomes. Translocations that activate the
human c-myc proto-oncogene involve Ig loci in B
cells and TcR loci in T cells.
28.5 Insertion, translocation, or amplification
may activate proto-oncogenes
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Figure 28.12 A chromosomal translocation is a
reciprocal event that exchanges parts of two
chromosomes. Translocations that activate the
human c-myc proto-oncogene involve Ig loci in B
cells and TcR loci in T cells.
28.5 Insertion, translocation, or amplification
may activate proto-oncogenes
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Figure 28.13 Translocations between chromosome 22
and chromosome 9 generate Philadelphia
chromosomes that synthesize bcr-abl fusion
transcripts that are responsible for two types of
leukemia.
28.5 Insertion, translocation, or amplification
may activate proto-oncogenes
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Figure 28.14 Oncogenes may code for secreted
proteins, transmembrane proteins, cytoplasmic
proteins, or nuclear proteins.
28.6 Oncogenes code for components of signal
transduction cascades
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Figure 28.14 Oncogenes may code for secreted
proteins, transmembrane proteins, cytoplasmic
proteins, or nuclear proteins.
28.6 Oncogenes code for components of signal
transduction cascades
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Figure 28.14 Oncogenes may code for secreted
proteins, transmembrane proteins, cytoplasmic
proteins, or nuclear proteins.
28.6 Oncogenes code for components of signal
transduction cascades
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Figure 26.14 Binding of ligand to the
extracellular domain can induce aggregation in
several ways. The common feature is that this
causes new contacts to form between the
cytoplasmic domains.
28.7 Growth factor receptor kinases and
cytoplasmic tyrosine kinases
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Figure 28.15 Activation of a growth factor
receptor involves ligand binding, dimerization,
and autophosphorylation. A truncated oncogenic
receptor that lacks the ligand-binding region is
constitutively active because it is not repressed
by the N-terminal domain.
28.7 Growth factor receptor kinases and
cytoplasmic tyrosine kinases
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Figure 28.14 Oncogenes may code for secreted
proteins, transmembrane proteins, cytoplasmic
proteins, or nuclear proteins.
28.7 Growth factor receptor kinases and
cytoplasmic tyrosine kinases
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Figure 28.16 A Src protein has an N-terminal
domain that associates with the membrane, a
modulatory domain that includes SH2 and SH3
motifs, a kinase catalytic domain, and (c-Src
only) a suppressor domain.
28.7 Growth factor receptor kinases and
cytoplasmic tyrosine kinases
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Figure 28.17 Two tyrosine residues are targets
for phosphorylation in Src proteins.
Phosphorylation at Tyr-527 of c-Src suppresses
autophosphorylation at Tyr-416, which is
associated with transforming activity. Only
Tyr-416 is present in v-Src. Transforming
potential of c-Src may be activated by removing
Tyr-527 or repressed by removing Tyr-416.
28.7 Growth factor receptor kinases and
cytoplasmic tyrosine kinases
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Figure 28.18 When a receptor tyrosine kinase is
activated, autophosphorylation generates a
binding site for the Src SH2 domain, Tyr-527 is
released and dephosphorylated, Tyr-416 becomes
phosphorylated, and Src kinase is activated.
28.7 Growth factor receptor kinases and
cytoplasmic tyrosine kinases
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Figure 28.19 Oncogenes that code for
transcription factors have mutations that
inactivate transcription (v-erbA and possibly
v-rel) or that activate transcription (v-jun and
v-fos).
28.8 Oncoproteins may regulate gene expression
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Figure 28.19 Oncogenes that code for
transcription factors have mutations that
inactivate transcription (v-erbA and possibly
v-rel) or that activate transcription (v-jun and
v-fos).
28.8 Oncoproteins may regulate gene expression
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Figure 28.19 Oncogenes that code for
transcription factors have mutations that
inactivate transcription (v-erbA and possibly
v-rel) or that activate transcription (v-jun and
v-fos).
28.8 Oncoproteins may regulate gene expression
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Figure 28.20 The adenovirus E1A region is spliced
to form three transcripts that code for
overlapping proteins. Domain 1 is present in all
proteins, domain 2 in the 289 and 243 residue
proteins, and domain 3 is unique to the 2The
adenovirus E1A region is spliced to form three
transcripts that code for overlapping proteins.
Domain 1 is present in all proteins, domain 2 in
the 289 and 243 residue proteins, and domain 3 is
unique to the 289 residue protein. The C-terminal
domain of the 55 residue protein is translated in
a different reading frame from the common
C-terminal domains of the other two proteins.
28.8 Oncoproteins may regulate gene expression
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Figure 28.21 Retinoblastoma is caused by loss of
both copies of the RB gene in chromosome band
13q14. In the inherited form, one chromosome has
a deletion in this region, and the second copy is
lost by somatic mutation in the individual. In
the sporadic form, both copies are lost by
individual somatic events.
28.9 RB is a tumor suppressor that controls the
cell cycle
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Figure 28.21 Retinoblastoma is caused by loss of
both copies of the RB gene in chromosome band
13q14. In the inherited form, one chromosome has
a deletion in this region, and the second copy is
lost by somatic mutation in the individual. In
the sporadic form, both copies are lost by
individual somatic events.
28.9 RB is a tumor suppressor that controls the
cell cycle
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Figure 28.22 A block to the cell cycle is
released when RB is phosphorylated (in the normal
cycle) or when it is sequestered by a tumor
antigen (in a transformed cell).
28.9 RB is a tumor suppressor that controls the
cell cycle
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Figure 28.23 Several components concerned with
G0/G1 or G1/S cycle control are found as tumor
suppressors.
28.9 RB is a tumor suppressor that controls the
cell cycle
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Figure 28.24 Wild-type p53 is required to
restrain cell growth. Its activity may be lost by
deletion of both wild-type alleles or by a
dominant mutation in one allele.
28.10 Tumor suppressor p53 suppresses growth or
triggers apoptosis
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Figure 28.24 Wild-type p53 is required to
restrain cell growth. Its activity may be lost by
deletion of both wild-type alleles or by a
dominant mutation in one allele.
28.10 Tumor suppressor p53 suppresses growth or
triggers apoptosis
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Figure 28.25 Damage to DNA activates p53. The
outcome depends on the stage of the cell cycle.
Early in the cycle, p53 activates a checkpoint
that prevents further progress until the damage
has been repaired. If it is too late to exercise
the checkpoint, p53 triggers apoptosis.
28.10 Tumor suppressor p53 suppresses growth or
triggers apoptosis
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Figure 28.26 Different domains are responsible
for each of the activities of p53.
28.10 Tumor suppressor p53 suppresses growth or
triggers apoptosis
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Figure 28.26 Different domains are responsible
for each of the activities of p53.
28.10 Tumor suppressor p53 suppresses growth or
triggers apoptosis
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Figure 28.27 53 activates several independent
pathways. Activation of cell cycle arrest
together with inhibition of genome instability is
an alternative to apoptosis.
28.10 Tumor suppressor p53 suppresses growth or
triggers apoptosis
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Figure 27.25 p21 and p27 inhibit assembly and
activity of cdk4,6-cyclin D and cdk2-cyclin E by
CAK. They also inhibit cycle progression
independent of RB activity. p16 inhibits both
assembly and activity of cdk4,6-cyclin D.
28.10 Tumor suppressor p53 suppresses growth or
triggers apoptosis
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Figure 28.23 Several components concerned with
G0/G1 or G1/S cycle control are found as tumor
suppressors.
28.10 Tumor suppressor p53 suppresses growth or
triggers apoptosis
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Figure 28.28 p53 activity is antagonized by mdm2,
which is neutralized by p19ARF.
28.10 Tumor suppressor p53 suppresses growth or
triggers apoptosis
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Figure 28.29 Each pathway that activates p53
causes modification of a particular set of
residues.
28.10 Tumor suppressor p53 suppresses growth or
triggers apoptosis
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Most tumors arise as the result of multiple
events. It is likely that some of these events
involve the activation of oncogenes, while others
take the form of inactivation of tumor
suppressors. The requirement for multiple events
reflects the fact that normal cells have multiple
mechanisms to regulate their growth and
differentiation, and several separate changes may
be required to bypass these controls.
28.11 Immortalization and transformation
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Indeed, the existence of many genes in which
single mutations were tumorigenic would no doubt
be deleterious to the organism, and has been
selected against. Nonetheless, oncogenes and
tumor suppressors define genes in which mutations
create a predisposition to tumors, that is, they
represent one of the necessary events.
28.11 Immortalization and transformation
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It is an open question as to whether the
oncogenes and tumor suppressor genes identified
in available assays are together sufficient to
account entirely for the occurrence of cancers,
but it is clear that their properties explain at
least many of the relevant events.
28.11 Immortalization and transformation
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1. A tumor cell is distinguished from a normal
cell by its immortality, morphological
transformation, and (sometimes) ability to
metastasize. 2. DNA tumor viruses carry
oncogenes without cellular counterparts. 3. Some
v-onc genes are qualitatively different from
their c-onc counterparts, since the v-onc gene is
oncogenic at low levels of protein, while the
c-onc gene is not active even at high levels. 4.
c-onc genes have counterpart v-onc genes in
retroviruses, but some proto-oncogenes have been
identified only by their association with
cellular tumors.
28.12 Summary
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5. Cellular oncoproteins may be derived from
several types of genes. 6. Growth factor
receptors located in the plasma membrane are
represented by truncated versions in v-onc genes.
7. Some oncoproteins are cytoplasmic tyrosine
kinases their targets are largely unknown. 8.
Ras proteins can bind GTP and are related to the
subunits of G proteins involved in signal
transduction across the cell membrane.
28.12 Summary
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9. Nuclear oncoproteins may be involved directly
in regulating gene expression, and include Jun
and Fos, which are part of the AP1 transcription
factor.10. Retinoblastoma (RB) arises when both
copies of the RB gene are deleted or
inactivated.11. p53 was originally classified as
an oncogene because missense mutations in it are
oncogenic. 12. p53 has a sequence-specific
DNA-binding domain that recognizes a palindromic
10 bp sequence.
28.12 Summary
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13. p53 is bound by viral oncogenes such as SV40
T antigen, whose oncogenic properties result, at
least in part, from the ability to block p53
function. 14. The locus INK4A contains two tumor
suppressors that together control both major
tumor suppressor pathways. 15. Loss of p53 may
be necessary for immortalization, because both
the G1 checkpoint and the trigger for apoptosis
are inactivated.
28.12 Summary