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1. Oncogenes and
tumour suppressor
genes

2. Introduction
 cell division process is dependent on a
tightly controlled sequence of events.
 dependent on the proper levels of
transcription and translation of certain
genes.
 When this process does not occur properly,
unregulated cell growth may be the end
result.

3. Mutation

4. Introduction
 Of the 30,000 or so genes that are currently
thought to exist in the human genome, there is
a small subset that seems to be particularly
important in the prevention, development, and
progression of cancer.
 These genes have been found to be either
malfunctioning or non-functioning in many
different kinds of cancer.
 The genes have been categorized into two
broad categories, depending on their normal
functions in the cell.

5.  Genes whose protein products stimulate
or enhance the division and viability of
cells. This first category also includes
genes that contribute to tumour growth
by inhibiting cell death.
 Genes whose protein products can
directly or indirectly prevent cell division
or lead to cell death.

6.  The normal versions of genes in the first
group (whose protein products stimulate or enhance the division
and viability of cells )are called proto-oncogenes.
 The mutated or otherwise damaged
versions of these genes are called
oncogenes.
 The genes in the second group (whose protein
products can directly or indirectly prevent cell division or lead to cell
death) are called tumour suppressors.

9.  tumour suppressors function in many
key cellular processes including the
regulation of transcription, DNA repair
and cell:cell communication.
 The loss of function of these genes
leads to abnormal cellular behavior.

10. DNA tumour viruses
 Important role in current understanding of
neoplasia.
 Viruses produce proteins - target key cellular
regulatory proteins
Rb, p53

11. tumour Suppressor Genes
 Some genes suppress tumour formation.
 Their protein product inhibits mitosis.
 When mutated, the mutant allele behaves as a
recessive; that is, as long as the cell contains
one normal allele, tumour suppression
continues.
 (Oncogenes, by contrast, behave as
dominants; one mutant, or overly-active, allele
can predispose the cell to tumour formation).

12. Example 1: RB - the retinoblastoma gene
 Retinoblastoma is a cancerous tumour of the
retina. It occurs in two forms:
Familial retinoblastoma
Multiple tumours in the retinas of both eyes
occurring in the first weeks of infancy.

13.  Mechanism. The Rb protein prevents cells from
entering S phase of the cell cycle. It does this
by binding to a transcription factor called
E2F.

14. Example 2: p53
 The product of the tumour suppressor gene
p53 is a protein of 53 kilodaltons (hence the
name).
 The p53 protein prevents a cell from completing
the cell cycle if
its DNA is damaged or
the cell has suffered other types of damage.
 When
the damage is minor, p53 halts the cell cycle —
hence cell division — until the damage is repaired.
the damage is major and cannot be repaired, p53
triggers the cell to commit suicide by apoptosis.

15.  These functions make p53 a key player in protecting
us against cancer; that is, an important tumour
suppressor gene.
 More than half of all human cancers do, in fact,
harbour p53 mutations and have no functioning p53
protein.

16. Loss Of Heterozygosity (LOH)
 Because tumour suppressor genes are
recessive, cells that contain one normal and
one mutated gene — that is, are heterozygous
— still behave normally.
 However, there are several mechanisms which
can cause a cell to lose its normal gene and
thus be predisposed to develop into a tumour.
These may result in a "loss of heterozygosity"
or "LOH".

17. Mechanisms of LOH:
1. Deletion of
the normal allele;
the chromosome arm containing the normal allele;
the entire chromosome containing the normal
allele (resulting in aneuploidy).
2. Loss of the chromosome containing the normal allele
followed by duplication of the chromosome containing
the mutated allele.
3. Mitotic recombination. The study of tumour suppressor
genes revealed (for the first time) that crossing over —
with genetic recombination — occasionally occurs in
mitosis (as it always does in meiosis).
In #2 and #3, the resulting cell now carries two copies of the
"bad" gene. This is called "reduction to homozygosity".

18. tumour suppressor genes = anti-oncogenes
 Genes like RB and p53 are also called anti-
oncogenes. They were first given this name
because they reverse, at least in cell culture,
the action of known oncogenes.

19. Human Papillomavirus (HPV)
Once inside the cells of their host, human
papilloma viruses synthesise
a protein designated E7 and
another designated E6.

20. Human Papillomavirus
 The E7 protein of one of these binds to the Rb
protein preventing it from binding to the host
transcription factor E2F.
Result: E2F is now free to bind to the promoters of genes
(like c-myc) that cause the cell to enter the cell cycle . Thus
this version of E7 is an oncogene product.
 The E6 protein of human papilloma virus implicated
in cervical cancer binds the p53 protein targeting it
for destruction by proteasomes and thus removing
the block on the host cell's entering the cell cycle.

21. Oncogenes
 Genes associated with the stimulation of cell
division.
 Cancers result from only one mutant allele of
gene.

23. Oncogenes
1. Growth Factors or Receptors for
Growth Factors
PDGF Platelet Derived Growth Factor
(brain and breast cancer)
erb-B receptor for epidermal growth
factor (brain and breast cancer)
erb-B2 receptor for growth factor
(breast, salivary, and ovarian cancers)
RET growth factor receptor (thyroid
cancer)

24. Oncogenes
3. Transcription Factors that Activate
Growth Promoting Genes
c-myc activates transcription of growth
stimulation genes (leukemia, breast,
stomach, and lung cancer)
N-myc (nerve and brain cancer)
L-myc (lung cancer)
c-jun and c-fos function as transcription
factors

25. MYC
 The myc protein acts as a transcription
factor and it controls the expression of
several genes.
 Mutations in the myc gene have been
found in many different cancers,
including Burkitt's lymphoma, B-cell
leukemia, and lung cancer.
 The myc family of oncogenes may
become activated by gene
rearrangement or amplification.

26.  Gene rearrangements involve the breakage
and re-sealing of chromosomes.
 This process can involve large amounts of DNA
and can affect many genes.
 The movement of a gene or group of genes to a
different location within the same chromosome
or to a different chromosome often leads to
altered gene expression and cell function.