ONCOGENES

SOME BASIC TERMINOLOGY

Oncogenesis = process of initiation of tumors (cancer) in an organism
(onkos = mass; genesis = birth)

Tumor = tissue composed of cells that deviate from normal program of cell
division and differentiation.

Benign tumor = tumor cells remain together in a single mass and do not
invade or disrupt surrounding tissues

Malignant tumor = tumor cells invade and disrupt surrounding tissues (and
are diagnosed as cancer).

Metastasis = spread of malignant tumor cells throughout the body (typically

through the blood and lymphatic system)
 INTRODUCTION
 An oncogene is a protein encoding gene,
which when deregulated participates in the
onset and development of cancer.
 HISTORY
Oncogenes
Rous had discovered the
first oncovirus, Rous sarcoma
virus, which causes sarcoma
in chickens.

 Investigation of
oncoviral genomes
revealed the presence
Rous
of oncogenes in these
viruses
 HISTORY
 The first oncogene was discovered in 1970 and was termed src
(pronounced sarc as in sarcoma). Src was in fact first discovered as
an oncogene in a chicken retrovirus.

 Experiments performed by Dr G. Steve Martin of the University of

California, Berkeley demonstrated that the SRC was indeed the
oncogene of the virus.

 In 1976, Drs. J. Michael Bishop and Harold E. Varmus of the

University of California, San Francisco demonstrated that oncogenes
were defective proto-oncogenes, found in many organisms including
humans.

 For this discovery ,Bishop and Varmus were awarded the Nobel Prize
in 1989.
 The basic concept
1. Oncogenes:
 These genes code for proteins that are capable of stimulating
cell growth and division.
 In normal tissues and organisms, such growth-stimulating
proteins are regulated, so that growth is appropriately limited.
 However, changes/mutation in these genes may result in loss
of growth regulation, leading to uncontrolled cell proliferation
and tumor development.
 These changed genes are known as oncogenes, because
they induce the oncogenic state — cancer.
 Oncogenes are dominant, because a change/mutation of only
one of the cell’s two copies of that gene can lead to tumor
formation.
2 . Proto-oncogenes:
 The normal precurcers of these above genes are
termed proto-oncogenes and are essential for
normal cell growth and differentiation.
 Proto-oncogenes are called as cellular oncogenes
also.
 . A proto-oncogene is a normal gene that can
become an oncogene due to mutations or
increased expression.
3 .Viral oncogenes:
 These genes are present in viruses, may lead to
uncontrolled cell proliferation and tumor
development.
 Virus oncogenes are homolog with that
corresponding cellular oncogenes.
4. Cancer suppressive genes:
 These genes code for proteins whose normal
function is to turn off cell growth.
 A change/mutation in one of these growth-limiting
genes may result in a protein product that has lost
its growth limiting ability.
 Cancer suppressive genes are called as tumor
suppressor genes or anti-oncogenes as well.
 The normal forms of such genes have been shown
to suppress tumor growth and are known as tumor
suppressor genes.
 Because both cellular copies of a tumor suppressor
gene must be mutated to foil its growth-limiting
action, these genes are recessive in nature.
Activation of proto-oncogene
 The proto-oncogene can become an oncogene by a
relatively small modification of its original function.
There are three basic activation types:
1.A mutation within a proto-oncogene can cause a
change in the protein structure, causing
 an increase in protein (enzyme) activity
 a loss of regulation
2.An increase in protein concentration, caused by
 an increase of protein expression (through misregulation)
 an increase of protein stability, prolonging its existence and
thus its activity in the cell
 a gene duplication (one type of chromosome abnormality),
resulting in an increased amount of protein in the cell
3. A chromosomal translocation (another type of
chromosome abnormality), causing
 an increased gene expression in the wrong cell type or
at wrong times
 the expression of a constitutively active hybrid protein.
This type of aberration in a dividing stem cell in the
bone marrow leads to adult leukemia.

 Mutations in microRNAs can lead to activation of

oncogenes. New research indicates that small
RNAs 21-25 nucleotides in length, called as
microRNAs (miRNAs) can control expression of
these genes by downregulating them.
Mechanism of activation
Mechanisms by which proto-oncogenes can be
converted to cellular oncogenes:
1. Quantitative: Tumor formation is induced by an
increase in the absolute number of proto-
oncogene products or by its production in
inappropriate cell types.
2. Qualitative: Conversion from proto-oncogene to
transforming gene (c-onc) with changes in the
nucleotide sequence which responsible for the
acquisition of the new properties.
Mechanism of activation of
proto- oncogenes
1. Point mutation
2.Gene amplification
3.Chromosomal translocation
4.DNA rearrangement
Mechanism 1: point mutation can convert
proto-oncogenes into oncogenes
 Difference of normal RAS gene (proto-oncogene)
and abnormal RAS gene (an oncogene): a single
nucleotide base
 RAS oncogene point mutation is detected in cancer
of bladder, lung, colon, pancrease, and thyroid
 Mutation of RAS gene by carcinogens: asbestos,
vinyl chloride, dimethylbenzanthracene

15
How Cellular Oncogenes Arise
 Mechanism 2: gene amplification can
convert proto-oncogenes into
oncogenes
 Replicating of DNA in specific chromosome
region
 The main types examined by light microscopy:
homogeneously staining regions (HSRs) and
double minutes (DMs)
 Amplified DNA containing from several dozen to
several hundred copies of one or more genes
 Most amplified genes are actively expressed
 Produce normal but excessive protein
 MYC gene family: MYC, MYCL, MYCN
 By gene amplification for human cancer
 ERBB2 gene amplification involved in 25% of
all breast and ovarian cancers
 MYCN gene amplication: neuroblastoma
Mechanism 3: chromosomal
translocation can convert proto-
oncogene into oncogene
 Philadelphia chromosome: chromosome 22
abnormal
 Associated with 90% chronic myelogeneous
leukemia (CML)
 Chromosome 9 and 22 reciprocal chromosome
exchange
 ABL and BCR gene (F. 9-4): BCR-ABL fusion
gene (in chromosome 22)
 fusion protein production
 Chromosome 3-5, 6-9, 7-11, 8-16, 9-12, 12-22,
16-21 translocation for cancer development
 Chromosome 8 and 14 translocation: Burkitt’s
lymphoma
 MYC proto-oncogene translocation
 Overexpression of normal Myc protein
How Cellular Oncogenes Arise

22
 Altered
chromosome 9

Normal
chromosome
9 Chromosome break
Normal
Altered
chromosome chromosome
22 22

bcr bcr-abl

abl

The altered chromosome 22 is called Philadelphia

chromosome
Mechanism 4: Local DNA rearrangements
can convert proto-oncogenes into
oncogenes
 DNA deletions, insertions, transpositions, and
inversions
 TRK oncogene: fusion gene
 Trk fusion protein
Proteins produced by
oncogenes
 Most of the proteins produced by oncogene
are components of signaling pathways that
promote cell proliferation and survival.
Oncogenes typically code for
components of signaling pathways
that activate cell proliferation
 Ras-MAPK pathway
Oncogenes and cell growth
 One example of signaling pathway - MAPK
growth factor

receptor tyrosine kinase

ras

kinase cascade (serine/threonine)

transcription factors
Since the signal passes from one component to the next,
inappropriate activation of one element in the cascade can
lead to widespread changes in gene expression.

These pathways are not strictly linear but branch and

interact with many other signaling pathways can cause
wider effects may require mutations in parallel
pathways to get oncogenesis.

Central importance of this pathway is illustrated by the

number of components that can be mutated into
oncogenes aberrant activation of mitogenic pathways can
contribute to oncogenicity.
Retroviruses and oncogenes:
Retrovirus =

 Single-stranded RNA virus that replicates via double-

stranded DNA intermediate.
 RNA is converted to cDNA by reverse transcriptase.
• DNA integrates into host chromosome and is
transcribed.
• Retroviruses typically possess:

• 2 copies of a 7-10 kb ssRNA genome

• protein viral core

• glycolipid envelope (glycoproteins recognize host

cells)
Fig. Structure of a retrovirus
Retroviruses and oncogenes:

• All RNA tumor viruses are retroviruses.

• RNA viral oncogenes are altered forms of normal host

genes that occur in the virus genome.

• Examples of retroviruses include:

• Rous sarcoma virus (RSV)

• Feline leukemia virus

• Mouse mammary tumor virus

• Human immunodeficiency virus (HIV)

Retroviruses and oncogenes:

Three types of genes occur in most retroviruses:

1. gag (group antigen): codes the protein core

2. pol (polymerase): codes reverse
transcriptase and an enzyme for proviral
integration.
3. env (envelope): codes envelope
glycoproteins.

Nononcogenic retroviruses possess no oncogenes

and direct their own life cycle (e.g., HIV infects
and destroys T helper cells).
Retroviruses and oncogenes:

Oncogenic retroviruses (v-onc) transform the cell and cause cancer

(also called transducing viruses)

• Different retroviruses carry different oncogenes responsible for

different types of cancer (e.g. v-src in RSV).

• Most oncogenic retroviruses (but not RSV) are defective and do not
possess a full set of virus life-cycle genes.

(transform cells but do not produce progeny viruses)

• Defective retroviruses produce progeny with the help of a normal

virus that co-infects cell and supplies missing gene products.

(helper virus supplies missing gene products -> viral expression)

How are retroviruses oncogenes created?

1. Retrovirus integrates into host chromosome near a cellular proto-oncogene

by random recombination.

2. Deletion fuses retrovirus transcription signal sequences with proto-oncogene

sequences.

3. In the process, parts of the viral DNA sequences typically are deleted (this is
how the defective oncogene is created).

4. Viral “progeny” carry the cellular gene, but now under the influence of viral
promoters.

5. Most transducing viral oncogenes are defective and cannot replicate

independently.

6. If mRNA is packaged into a virus particle along with a normal virus genome
(co-infection), reverse transcriptase produces a new defective oncogene by
switching templates during cDNA synthesis.

7. Template switching + lack of proofreading during DNA replication result in

rapid evolution of oncogenic retroviruses.
Fig, Formation of a transducing retrovirus oncogene.