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Proto-Oncogenes, Oncogenes, and
Tumor-Suppressor Genes
58
A. DEFINITIONS
1.
A proto-oncogene is a normal gene that encodes a protein involved in stimulation
of the cell cycle. Because the cell cycle can be regulated at many different points,
proto-oncogenes fall into many different classes (i.e., growth factors, receptors,
signal transducers, and transcription factors).
2.
An oncogene is a mutated proto-oncogene that encodes for an oncoprotein in-
volved in the hyperstimulation of the cell cycle leading to oncogenesis. This is
because the mutations cause an increased activity of the oncoprotein (either a
hyperactive oncoprotein or increased amounts of normal protein), not a loss of
activity of the oncoprotein.
B. ALTERATION OF A PROTO-ONCOGENE TO AN ONCOGENE. We know now that
the vast majority of human cancers are not caused by viruses. Instead, most human
cancers are caused by the alteration of proto-oncogenes so that oncogenes are formed
producing an oncoprotein. The mechanisms by which proto-oncogenes are altered
include.
1.
Point mutation.
A point mutation (i.e., a gain-of-function mutation) of a proto-
oncogene leads to the formation of an oncogene. A single mutant allele is suffi-
cient to change the phenotype of a cell from normal to cancerous (i.e., a dominant
mutation). This results in a hyperactive oncoprotein that hyperstimulates the cell
cycle leading to oncogenesis. Note: proto-oncogenes only require a mutation in one
allele for the cell to become oncogenic, whereas tumor-suppressor genes require a
mutation in both alleles for the cell to become oncogenic.
2.
Translocation.
A translocation results from breakage and exchange of segments
between chromosomes. This may result in the formation of an oncogene (also
called a fusion gene or chimeric gene) which encodes for an oncoprotein (also called
a fusion protein or chimeric protein). A good example is seen in chronic myeloid
leukemia (CML). CML t(9;22)(q34;q11) is caused by a reciprocal translocation
between chromosomes 9 and 22 with breakpoints at q34 and q11, respectively. The
resulting der(22) is referred to as the Philadelphia chromosome. This results in a
hyperactive oncoprotein that hyperstimulates the cell cycle leading to oncogenesis.
3.
Amplification.
Cancer cells may contain hundreds of extra copies of proto-
oncogenes. These extra copies are found as either small paired chromatin bodies
separated from the chromosomes or as insertions within normal chromosomes.
This results in increased amounts of normal protein that hyperstimulates the cell
cycle leading to oncogenesis.
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PROTO-ONCOGENES, ONCOGENES, AND TUMOR-SUPPRESSOR GENES
4.
Translocation into a transcriptionally active region.
A translocation results
from breakage and exchange of segments between chromosomes. This may result
in the formation of an oncogene by placing a gene in a transcriptionally active re-
gion. A good example is seen in Burkitt lymphoma. Burkitt lymphoma
t(8;14)(q24;q32) is caused by a reciprocal translocation between band q24 on
chromosome 8 and band q32 on chromosome 14. This results in placing the MYC
gene on chromosome 8q24 in close proximity to the IGH gene locus (i.e., an im-
munoglobulin gene locus) on chromosome 14q32, thereby putting the MYC gene
in a transcriptionally active area in B lymphocytes (or antibody-producing plasma
cells). This results in increased amounts of normal protein that hyperstimulates
the cell cycle leading to oncogenesis.
C. MECHANISM OF ACTION OF THE RAS GENE: A PROTO-ONCOGENE (Figure 9-1).
The diagram shows the RAS proto-oncogene and RAS oncogene action.
1.
The RAS proto-oncogene encodes a nor-
mal G-protein with GTPase activity. The G
protein is attached to the cytoplasmic face
of the cell membrane by a lipid called far-
nesyl isoprenoid. When a hormone binds
to its receptor, the G protein is activated.
The activated G protein binds GTP which
stimulates the cell cycle. After a brief pe-
riod, the activated G protein splits GTP
into GDP and phosphate such that the
stimulation of the cell cycle is terminated.
2.
If the RAS proto-oncogene undergoes a
mutation, it forms the RAS oncogene. The
RAS oncogene encodes an abnormal G
protein (RAS oncoprotein) where a glycine
is changed to a valine at position 12. The
RAS oncoprotein binds GTP which stimu-
lates the cell cycle. However, the RAS on-
coprotein cannot split GTP into GDP and
phosphate so that the stimulation of the
cell cycle is never terminated.
● Figure 9-1 Action of RAS Gene.
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CHAPTER 9
A tumor-suppressor gene is a normal gene that encodes a
protein involved in suppression of the cell cycle. Many human cancers are caused by loss-
of-function mutations of tumor-suppressor genes. Note: tumor-suppressor genes require a
mutation in both alleles for a cell to become oncogenic, whereas, proto-oncogenes only
require a mutation in one allele for a cell to become oncogenic. Tumor-suppressor genes
can be either “gatekeepers” or “caretakers.”
A. GATEKEEPER TUMOR-SUPPRESSOR GENES. These genes encode for proteins that
either regulate the transition of cells through the checkpoints (“gates”) of the cell cycle
or promote apoptosis. This prevents oncogenesis. Loss-of-function mutations in gate-
keeper tumor-suppressor genes lead to oncogenesis.
A LIST OF PROTO-ONCOGENES
TABLE
9-1
Protein Encoded by
Cancer Associated with Mutations
Class
Proto-Oncogene
Gene
of the Proto-Oncogene
Growth Platelet-derived
growth
PDGFB
Astrocytoma, osteosarcoma
factors
factor (PDGF)
Fibroblast growth factor
FGF4
Stomach carcinoma
Receptors
Epidermal growth factor
EGFR
Squamous cell carcinoma of lung; breast,
receptor (EGFR)
ovarian, and stomach cancers
Receptor tyrosine kinase
RET
Multiple endocrine adenomatosis 2
Receptor tyrosine kinase
MET
Hereditary papillary renal carcinoma,
hepatocellular carcinoma
Receptor tyrosine kinase
KIT
Gastrointestinal stromal tumors
Receptor tyrosine kinase
ERBB2
Neuroblastoma, breast cancer
Signal Tyrosine
kinase
ABL/BCR
CML t(9;22)(q34;q11)*
transducers
Serine/threonine kinase
BRAF
Melanoma, colorectal cancer
RAS G-proteins
HRAS
Lung, colon, and pancreas cancers
KRAS
NRAS
Transcription
Leucine zipper protein
FOS
Finkel-Biskes-Jinkins osteosarcoma
factors
Leucine zipper protein
JUN
Avian sarcoma 17
Helix-loop-helix protein
N-MYC
Neuroblastoma
Helix-loop-helix protein
L-MYC
Lung carcinoma
Helix-loop-helix protein
MYC
Burkitt lymphoma t(8;14)(q24;q32)
Retinoic acid receptor
PML/RAR
APL t(15;17)(q22;q12)
Transcription factor
FUS/ERG
AML t(16;21)(p11;q22)
Transcription factor
PBX/TCF3
Pre-B cell ALL t(1;19)(q21;p13.3)
Transcription factor
FOX04/MLL
ALL t(X;11)(q13;q23)
Transcription factor
FLI1/EWSR1
Ewing sarcoma t(11;22)(q24;q12)
PDGFB
platelet-derived growth factor beta gene; FGF4 fibroblast growth factor 4 gene; EGFR epidermal growth factor
receptor gene; RET
rearranged during transfection gene; MET met proto-oncogene (hepatocyte growth factor receptor);
KIT
v-kit Hardy-Zuckerman 4 feline sarcoma viral oncogene homolog; ERBB2 v-erb-b2 erythroblastic leukemia viral oncogene
homolog 2; ABL/BCR
Abelson murine leukemia/breakpoint cluster region oncogene; BRAF v-raf murine sarcoma viral
oncogene homolog B1; HRAS
Harvey rat sarcoma viral oncogene homolog; KRAS Kirsten rat sarcoma 2 viral oncogene
homolog; NRAS
neuroblastoma rat sarcoma viral oncogene homolog; FOS Finkel-Binkes-Jinkins osteosarcoma; N-MYC
neuroblastoma v-myc myelocytomatosis viral oncogene homolog; MYC
v-myc myelocytomatosis viral oncogene homolog;
PML/RAR
promyelocytic leukemia/retinoic acid receptor alpha; FUS/ERG fusion (involved in t(12;16) in malignant
liposarcoma)/v-ets erythroblastosis virus E26 oncogene homolog; PBX/TCF3
pre-B-cell leukemia homeobox/transcription factor 3
(E2A immunoglobulin enhancer binding factors E12/E47); FOX04/MLL
forkhead box O4/myeloid/lymphoid or mixed-lineage
leukemia; FLI1/EWSR1
Friend leukemia virus integration 1/Ewing sarcoma breakpoint region 1.
ALL
acute lymphoblastoid leukemia; CML chronic myeloid leukemia; APL acute promyelocytic leukemia; AML acute myel-
ogenous leukemia.
D. A LIST OF PROTO-ONCOGENES (Table 9-1)
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PROTO-ONCOGENES, ONCOGENES, AND TUMOR-SUPPRESSOR GENES
B. CARETAKER TUMOR-SUPPRESSOR GENES. These genes encode for proteins that
either detect/repair DNA mutations or promote normal chromosomal disjunction dur-
ing mitosis. This prevents oncogenesis by maintaining the integrity of the genome.
Loss-of-function mutations in caretaker tumor-suppressor genes lead to oncogenesis.
C. MECHANISM OF ACTION OF THE RB1
GENE: A TUMOR-SUPPRESSOR GENE
(RETINOBLASTOMA; Figure 9-2). The dia-
gram shows RB1 tumor-suppressor gene action.
1.
The RB1 tumor-suppressor gene is located
on chromosome 13q14.1 and encodes for
normal RB protein that will bind to E2F
(a gene regulatory protein) such that there
will be no expression of target genes
whose gene products stimulate the cell cy-
cle. Therefore, there is suppression of the
cell cycle at the G1 checkpoint.
2.
A mutation of the RB1 tumor-suppressor
gene will encode an abnormal RB protein
that cannot bind E2F (a gene regulatory
protein) such that there will be expression
of target genes whose gene products stim-
ulate the cell cycle. Therefore, there is no
suppression of the cell cycle at the G1
checkpoint. This leads to the formation of
a retinoblastoma tumor.
● Figure 9-2 Action of RB1 Gene.
3.
There are two types of retinoblastomas.
a.
In hereditary retinoblastoma (RB), the individual inherits one mutant copy
of the RB1 gene from his parents (an inherited germline mutation). A somatic
mutation of the second copy of the RB1 gene may occur later in life within
many cells of the retina leading to multiple tumors in both eyes.
b.
In nonhereditary RB, the individual does not inherit a mutant copy of the RB1
gene from his parents. Instead, two subsequent somatic mutations of both
copies of the RB1 gene may occur within one cell of the retina leading to one
tumor in one eye. This has become known as Knudson’s two-hit hypothesis
and serves as a model for cancers involving tumor-suppressor genes.
D. MECHANISM OF ACTION OF THE TP53
GENE: A TUMOR-SUPPRESSOR GENE
(“GUARDIAN OF THE GENOME”) (Figure
9-3). The diagram shows TP53 tumor-sup-
pressor gene action.
1.
The TP53 tumor-suppressor gene is lo-
cated on chromosome 17p13 and encodes
for normal p53 protein (a zinc finger
gene regulatory protein) that will cause
the expression of target genes whose gene
products suppress the cell cycle at G1 by
inhibiting Cdk-cyclin D and Cdk-cyclin
E. Therefore, there is suppression of the
cell cycle at the G1 checkpoint.
2.
A mutation of TP53 tumor-suppressor gene
will encode an abnormal p53 protein that
will cause no expression of target genes
whose gene products suppress the cell
● Figure 9-3 Action of TP53 Gene.
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1.
Hereditary RB is an autosomal dominant
genetic disorder caused by a mutation in
the RB1 gene on chromosome 13q14.1-
q14.2 for the RB-associated protein
(p110
RB
). More than 1000 different muta-
tions of the RB1 gene have been identified,
which include missense, frameshift, and
RNA splicing mutations which result in a
premature STOP codon and a loss-of-
function mutation.
2.
RB protein binds to E2F (a gene regula-
tory protein) such that there will be no ex-
pression of target genes whose gene prod-
ucts stimulate the cell cycle at the G1
checkpoint. The RB protein belongs to the
family of tumor-suppressor genes.
3.
Hereditary RB affected individuals inherit
one mutant copy of the RB1 gene from their
parents (an inherited germline mutation)
followed by a somatic mutation of the sec-
ond copy of the RB1 gene later in life.
● Figure 9-4 Hereditary Retinoblastoma.
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CHAPTER 9
cycle. Therefore, there is no suppression of the cell cycle at the G1 checkpoint. The
TP53 tumor-suppressor gene is the most common target for mutation in human can-
cers. The TP53 tumor-suppressor gene plays a role in Li-Fraumeni syndrome.
E.
A LIST OF TUMOR-SUPPRESSOR GENES (Table 9-2)
A LIST OF TUMOR-SUPPRESSOR GENES
TABLE
9-2
Protein Encoded by
Cancer Associated with Mutations
Class
Tumor-Suppressor Gene
Gene
of the Tumor-Suppressor Gene
Gatekeeper
Retinoblastoma associated
RB1
Retinoblastoma, carcinomas of the
protein p110
RB
breast, prostate, bladder, and lung
Tumor protein 53
TP53
Li-Fraumeni syndrome; most human
cancers
Neurofibromin protein
NF1
Neurofibromatosis type 1, Schwannoma
Adenomatous polyposis
APC
Familial adenomatous polyposis coli,
coli protein
carcinomas of the colon
Wilms tumor protein 2
WT2
Wilms tumor (most common renal
malignancy of childhood)
Von Hippel-Lindau disease
VHL
Von Hippel-Lindau disease, retinal and
tumor-suppressor protein
cerebellar hemangioblastomas
Caretaker
Breast cancer type 1
BRCA1
Breast and ovarian cancer
susceptibility protein
Breast cancer type 2
BRCA2
Breast cancer in BOTH breasts
susceptibility protein
DNA mismatch repair
MLH1
Hereditary nonpolyposis colon cancer
protein MLH1
DNA mismatch repair
MSH2
Hereditary nonpolyposis colon cancer
protein MSH2
APC
familial adenomatous polyposis coli; VHL von Hippel-Lindau disease; WT Wilms tumor; NF-1 neurofibromatosis;
BRCA
breast cancer; RB retinoblastoma; TP53 tumor protein; MLH1 mut L homolog 1; MSH2 mut S homolog 2.
A. HEREDITARY RETINOBLASTOMA (Figure 9-4)
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