PROTO-ONCOGENES AND TUMOUR SUPPRSSOR GENES
ARTICLE
Proto-oncogenes and tumour-suppressor genes play a key role in cancer induction. These genes encode
many kinds of protein that help control cell growth and proliferation; mutations in these gene can
contribute to the development of cancer.
Conversion of Proto-Oncogenes into Oncogenes
o Oncogene is any gene that encodes a protein able to transform cells in culture or to induce cancer in
animals.
o Of the many known oncogenes, all but a few are derived from normal cellular genes (i.e. proto-
oncogenes) whose products participate in cellular growth- controlling pathways.
o Conversion, or activation, of a proto-oncogene generally involves a gain-of function mutation. At least
three mechanisms can produce oncogenes from the corresponding proto-oncogenes:
a. Point mutations in a proto-oncogene that results in a constitutively acting protein product.
b. Localized reduplication (gene amplification) of a DNA segment that includes a proto-
oncogenes, leading to overexpression of the encoded protein.
c. Chromosomal translocation that brings a growth-regulatory gene under the control of a
different promoter and that causes inappropriate expression of the gene.
o An oncogene formed by the first mechanism encodes an oncoprotein that differs slightly from the
normal protein encoded by the corresponding proto-oncogene.
o In contrast, the two mechanisms generate oncogenes whose protein products are identical with the
normal proteins; their oncogenic effect is due to their being expressed at higher-than normal levels or
in cell where they normally are not expressed.
Oncogenes Were First Identified in Cancer-Causing Retroviruses
RSV and other oncogenic viruses are thought to have arisen by incorporating, or transducing, a normal
cellular protooncogene into their genome. Subsequent mutation in the transduced gene then converted
it into an oncogene.
v-Src protein is a constitutively active mutant form of c-Src protein, a protein tyrosine kinase. In cells
containing an integrated RSC genome, not only is v-src transcribed at inappropriately high rate levels,
but the unregulated activity of v-Src protein causes continuous and inappropriate phosphorylation of
target proteins.
Because v-scr can induce cell transformation in the presence of the normal c-src is said to be a
dominant gain of function mutant of c-src.
Many other oncogenes derived from cellular proto-oncogenes have been found in different
retroviruses, implying that the normal vertebrate genome contains many potential cancer-causing
genes.
Many of these cancer-causing genes are also found in various animal retroviruses.
Slow-Acting Carcinogenic Retroviruses Can Activate Cellular Proto-Oncogenes
Because its genome carries the v-src oncogene, Rous sarcoma virus induces tumour within days.
Most oncogenic retroviruses, however, induce cancer only after a period of months or years.
The genomes of the slow-acting retroviruses differ from those of transducing viruses such as RSV in
one crucial respect; they lack an oncogene. Thus, slow-acting, or ‘long latency’, retroviruses have no
direct effect on growth of cells in culture.
The mechanism by which avian leukosis viruses cause cancer appears to operate in all slow-acting
retroviruses. Like other retroviruses, avian leukosis virus DNA generally integrates into cellular
chromosomes more or less at random. However, the finding that the site of integration in the cells
from tumors caused by these viruses is near the c-myc gene suggested that these slow-acting viruses
cause disease by activating expression of c-Myc, which is required for transcription of many genes that
encode cell cycle proteins.
, Whether the inserted proviral DNA acts as a promoter or enhancer of c-myc transcription, the
expressed c-Myc protein apparently is perfectly normal. The enhanced level of c-Myc resulting from
the strong promoting or enhancing activity of the retroviral LTR partly explains the oncogenic effect
of avian leukosis viruses.
Oncogene activation mechanisms (promoter insertion and enhancer insertion) operate in a variety of
oncogenes and have been implicated in many animal tumours induced by slow-acting retroviruses.
Many DNA Viruses Also Contain Oncogenes
Most animal cells infected by small DNA viruses such as SV40 are killed, but a very small proportion
integrate the viral DNA into the host-cell genome.
Although these cells survive infection, they become permanently transformed because the viral DNA
contains one or more oncogenes.
Loss of Function Mutations in Tumor-Suppressor Genes are Oncogenic
Tumour suppressor genes generally encode proteins that in one way or another inhibit cell
proliferation.
Loss of one or more of these ‘brakes’ contributes to the development of many cancers.
Five broad classes of proteins are generally recognized as being encoded by tumor-suppressor genes:
Intracellular proteins, such as the p16 cyclin-kinase inhibitor, that regulate or inhibit
progression through a specific stage of the cell cycle.
Receptors for secreted hormones (e.g. tumour derived growth factor beta) that
function to inhibit cell proliferation.
Checkpoint-control proteins that arrest the cell cycle if DNA is damaged or
chromosomes are abnormal.
Proteins that promote apoptosis.
Enzymes that participate in DNA repair.
Loss of function mutations in the genes encoding DNA- repair enzymes promote inactivation of other
tumor-suppressor genes as well as activation of oncogenes.
Since generally one copy of a tumour-suppressor gene suffices to control cell proliferation, both alleles
of a tumor-suppressor gene must be lost or inactivated in order to promote tumor development. Thus
oncogenic loss of function mutations in tumour suppressor genes act recessively.
Tumour suppressor genes in many cancers have deletions or point mutations that prevent production of
any protein or lead to production of a non-functional protein.
The First Tumour-Suppressor Gene was Identified in Patients with Inherited Retinoblastoma
Inheriting one mutant allele of another tumour-suppressor gene increases to almost 100% the
probability that a person will develop a specific tumor.
Retinoblastoma is caused by loss of function of RB, the first tumour suppressor gene to be identified.
Protein encoded by RB helps regulate progress through the cell cycle.
A finding shows that the defective RB allele is acting recessively at the cellular level, and that other
genetic events are needed to bring on the transformed state.
One essential event is the deletion or mutation of the normal RB gene on the other chromosome,
giving rise to a cell that produces no functional Rb protein.
Hereditary retinoblastoma is inherited as an autosomal dominant trait.
Breast cancer also has a hereditary predisposition. Inheriting one mutant BRCA1 allele have 60%
probability of developing breast cancer. BRCA1 generally is not mutated in sporadic, noninhibited
breast cancer.
Loss of Heterozygosity of Tumor-Suppressor Genes Occurs by Mitotic Recombination or
Chromosome Mis-segregation
ARTICLE
Proto-oncogenes and tumour-suppressor genes play a key role in cancer induction. These genes encode
many kinds of protein that help control cell growth and proliferation; mutations in these gene can
contribute to the development of cancer.
Conversion of Proto-Oncogenes into Oncogenes
o Oncogene is any gene that encodes a protein able to transform cells in culture or to induce cancer in
animals.
o Of the many known oncogenes, all but a few are derived from normal cellular genes (i.e. proto-
oncogenes) whose products participate in cellular growth- controlling pathways.
o Conversion, or activation, of a proto-oncogene generally involves a gain-of function mutation. At least
three mechanisms can produce oncogenes from the corresponding proto-oncogenes:
a. Point mutations in a proto-oncogene that results in a constitutively acting protein product.
b. Localized reduplication (gene amplification) of a DNA segment that includes a proto-
oncogenes, leading to overexpression of the encoded protein.
c. Chromosomal translocation that brings a growth-regulatory gene under the control of a
different promoter and that causes inappropriate expression of the gene.
o An oncogene formed by the first mechanism encodes an oncoprotein that differs slightly from the
normal protein encoded by the corresponding proto-oncogene.
o In contrast, the two mechanisms generate oncogenes whose protein products are identical with the
normal proteins; their oncogenic effect is due to their being expressed at higher-than normal levels or
in cell where they normally are not expressed.
Oncogenes Were First Identified in Cancer-Causing Retroviruses
RSV and other oncogenic viruses are thought to have arisen by incorporating, or transducing, a normal
cellular protooncogene into their genome. Subsequent mutation in the transduced gene then converted
it into an oncogene.
v-Src protein is a constitutively active mutant form of c-Src protein, a protein tyrosine kinase. In cells
containing an integrated RSC genome, not only is v-src transcribed at inappropriately high rate levels,
but the unregulated activity of v-Src protein causes continuous and inappropriate phosphorylation of
target proteins.
Because v-scr can induce cell transformation in the presence of the normal c-src is said to be a
dominant gain of function mutant of c-src.
Many other oncogenes derived from cellular proto-oncogenes have been found in different
retroviruses, implying that the normal vertebrate genome contains many potential cancer-causing
genes.
Many of these cancer-causing genes are also found in various animal retroviruses.
Slow-Acting Carcinogenic Retroviruses Can Activate Cellular Proto-Oncogenes
Because its genome carries the v-src oncogene, Rous sarcoma virus induces tumour within days.
Most oncogenic retroviruses, however, induce cancer only after a period of months or years.
The genomes of the slow-acting retroviruses differ from those of transducing viruses such as RSV in
one crucial respect; they lack an oncogene. Thus, slow-acting, or ‘long latency’, retroviruses have no
direct effect on growth of cells in culture.
The mechanism by which avian leukosis viruses cause cancer appears to operate in all slow-acting
retroviruses. Like other retroviruses, avian leukosis virus DNA generally integrates into cellular
chromosomes more or less at random. However, the finding that the site of integration in the cells
from tumors caused by these viruses is near the c-myc gene suggested that these slow-acting viruses
cause disease by activating expression of c-Myc, which is required for transcription of many genes that
encode cell cycle proteins.
, Whether the inserted proviral DNA acts as a promoter or enhancer of c-myc transcription, the
expressed c-Myc protein apparently is perfectly normal. The enhanced level of c-Myc resulting from
the strong promoting or enhancing activity of the retroviral LTR partly explains the oncogenic effect
of avian leukosis viruses.
Oncogene activation mechanisms (promoter insertion and enhancer insertion) operate in a variety of
oncogenes and have been implicated in many animal tumours induced by slow-acting retroviruses.
Many DNA Viruses Also Contain Oncogenes
Most animal cells infected by small DNA viruses such as SV40 are killed, but a very small proportion
integrate the viral DNA into the host-cell genome.
Although these cells survive infection, they become permanently transformed because the viral DNA
contains one or more oncogenes.
Loss of Function Mutations in Tumor-Suppressor Genes are Oncogenic
Tumour suppressor genes generally encode proteins that in one way or another inhibit cell
proliferation.
Loss of one or more of these ‘brakes’ contributes to the development of many cancers.
Five broad classes of proteins are generally recognized as being encoded by tumor-suppressor genes:
Intracellular proteins, such as the p16 cyclin-kinase inhibitor, that regulate or inhibit
progression through a specific stage of the cell cycle.
Receptors for secreted hormones (e.g. tumour derived growth factor beta) that
function to inhibit cell proliferation.
Checkpoint-control proteins that arrest the cell cycle if DNA is damaged or
chromosomes are abnormal.
Proteins that promote apoptosis.
Enzymes that participate in DNA repair.
Loss of function mutations in the genes encoding DNA- repair enzymes promote inactivation of other
tumor-suppressor genes as well as activation of oncogenes.
Since generally one copy of a tumour-suppressor gene suffices to control cell proliferation, both alleles
of a tumor-suppressor gene must be lost or inactivated in order to promote tumor development. Thus
oncogenic loss of function mutations in tumour suppressor genes act recessively.
Tumour suppressor genes in many cancers have deletions or point mutations that prevent production of
any protein or lead to production of a non-functional protein.
The First Tumour-Suppressor Gene was Identified in Patients with Inherited Retinoblastoma
Inheriting one mutant allele of another tumour-suppressor gene increases to almost 100% the
probability that a person will develop a specific tumor.
Retinoblastoma is caused by loss of function of RB, the first tumour suppressor gene to be identified.
Protein encoded by RB helps regulate progress through the cell cycle.
A finding shows that the defective RB allele is acting recessively at the cellular level, and that other
genetic events are needed to bring on the transformed state.
One essential event is the deletion or mutation of the normal RB gene on the other chromosome,
giving rise to a cell that produces no functional Rb protein.
Hereditary retinoblastoma is inherited as an autosomal dominant trait.
Breast cancer also has a hereditary predisposition. Inheriting one mutant BRCA1 allele have 60%
probability of developing breast cancer. BRCA1 generally is not mutated in sporadic, noninhibited
breast cancer.
Loss of Heterozygosity of Tumor-Suppressor Genes Occurs by Mitotic Recombination or
Chromosome Mis-segregation
