Chapter 28
Oncogenes
and
cancer
28.1 Introduction
28.2 Transforming viruses carry oncogenes
28.3 Early genes of DNA transforming viruses have multifunction oncogenes
28.4 Retroviruses activate or incorporate cellular genes
28.5 Retroviral oncogenes have cellular counterparts
28.6 Ras oncogenes can be detected in a transfection assay
28.7 Ras proto-oncogenes can be activated by mutation at specific positions
28.8 Nondefective retroviruses activate proto-oncogenes
28.9 Proto-oncogenes can be activated by translocation
28.10 The Philadelphia translocation generates a new oncogene
28.11 Oncogenes code for components of signal transduction cascades
28.12 Growth factor receptor kinases can be mutated to oncogenes
28.13 Src is the prototype for the proto-oncogenic cytoplasmic tyrosine kinases
28.14 Oncoproteins may regulate gene expression
28.15 RB is a tumor suppressor that controls the cell cycle
28.16 Tumor suppressor p53 suppresses growth or triggers apoptosis
28.17 p53 is a DNA-binding protein
28.18 p53 is controlled by other tumor suppressors and oncogenes
28.19 Immortalization and transformation are independent
28.20 Telomere shortening causes cell mortality
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
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
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
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
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
Figure 28.3 Transforming viruses may carry oncogenes.
28.2 Transforming viruses carry oncogenes
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
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
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
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
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
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
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
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
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
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
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
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
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
Reciprocal translocation exchanges
part of one chromosome with part
of another chromosome.
28.5 Insertion,translocation,or amplification
may activate proto-oncogenes
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
Figure 28.26 Different
domains are
responsible for each of
the activities of p53.
28.10 Tumor
suppressor p53
suppresses growth or
triggers apoptosis
Figure 28.26 Different
domains are
responsible for each of
the activities of p53.
28.10 Tumor
suppressor p53
suppresses growth or
triggers apoptosis
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
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
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
Figure 28.28 p53
activity is antagonized
by mdm2,which is
neutralized by p19ARF.
28.10 Tumor suppressor
p53 suppresses growth or
triggers apoptosis
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
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
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
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
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
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
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
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
Oncogenes
and
cancer
28.1 Introduction
28.2 Transforming viruses carry oncogenes
28.3 Early genes of DNA transforming viruses have multifunction oncogenes
28.4 Retroviruses activate or incorporate cellular genes
28.5 Retroviral oncogenes have cellular counterparts
28.6 Ras oncogenes can be detected in a transfection assay
28.7 Ras proto-oncogenes can be activated by mutation at specific positions
28.8 Nondefective retroviruses activate proto-oncogenes
28.9 Proto-oncogenes can be activated by translocation
28.10 The Philadelphia translocation generates a new oncogene
28.11 Oncogenes code for components of signal transduction cascades
28.12 Growth factor receptor kinases can be mutated to oncogenes
28.13 Src is the prototype for the proto-oncogenic cytoplasmic tyrosine kinases
28.14 Oncoproteins may regulate gene expression
28.15 RB is a tumor suppressor that controls the cell cycle
28.16 Tumor suppressor p53 suppresses growth or triggers apoptosis
28.17 p53 is a DNA-binding protein
28.18 p53 is controlled by other tumor suppressors and oncogenes
28.19 Immortalization and transformation are independent
28.20 Telomere shortening causes cell mortality
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
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
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
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
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
Figure 28.3 Transforming viruses may carry oncogenes.
28.2 Transforming viruses carry oncogenes
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
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
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
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
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
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
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
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
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
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
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
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
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
Reciprocal translocation exchanges
part of one chromosome with part
of another chromosome.
28.5 Insertion,translocation,or amplification
may activate proto-oncogenes
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
Figure 28.26 Different
domains are
responsible for each of
the activities of p53.
28.10 Tumor
suppressor p53
suppresses growth or
triggers apoptosis
Figure 28.26 Different
domains are
responsible for each of
the activities of p53.
28.10 Tumor
suppressor p53
suppresses growth or
triggers apoptosis
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
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
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
Figure 28.28 p53
activity is antagonized
by mdm2,which is
neutralized by p19ARF.
28.10 Tumor suppressor
p53 suppresses growth or
triggers apoptosis
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
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
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
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
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
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
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
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
