Download proto-oncogene

Cancer &Oncogenes
Objectives
• Define the terms oncogene, proto-oncogenes and
growth factors giving examples.
• Describe the mechanisms of activations of protooncogenes and their roles in carcinogenesis.
Reference:
Textbook of Medical Biochemistry, 7th edition. Section 7,
chapter46 (Biochemistry of cancer). Pages:737-744.
Define proto-oncogenes oncogene,and
growth factors
* A proto-oncogene is a normal gene that can
become an oncogene due to mutations or
increased expression. The proto-onncogenes
converted to ocogenes and develop cancer.
* A mutant proto-oncogene whose protien product
is involved in the transformation of normal cell to
cancer cell.
* An oncogene can be defined as an altered gene
whose product acts in a dominant manner to
accelerate cell growth or cell division.
Carcinogenesis
Oncogenes and Tumor Suppressor Genes
In normal cell, two categories of cell regulatory genes:
• Proto-oncogenes (cellular oncogene, c-onc)
• Tumor suppressor gene
Proto-oncogenes  oncogenes
 increase growth rate  cancer
Tumor suppressor genes inactivated  cancer
Proto-oncogenes code for:
• Growth factors
• Receptors
• Signal transduction factors
Differences between oncogenes & Tumor
suppressor genes
Oncogenes
Mutation in one of the two
alleles is sufficient
Tumor suppressor genes
Both alleles must be affected
Gain of function of a protein that Loss of function of protein
signals cell division
Mutation arises in somatic cells,
not inherited
Mutation present in germ cell
(inherited ) or in somatic cell
Some tissue preference
Often strong tissue preference
NORMAL CELL
Growth factor
Growth factor receptor
cytoplasm
Signal transduction
nucleus
Activation of
transcription
Relationship between gene products of
proto oncogene
Growth factors eg IGF
Growth factor receptors
Eg erb-2, ret
Signal transducing
factors
Eg cytoplasmic
kinases
cell cycle
proteins eg
cyclin D
DNA binding
proteins
concerned with
transcription
Tumor suppressor gene (antioncogenes):
• It is a gene that protects a cell from cancer.
– Tumor suppressor genes code for factors that downregulate the cell cycle
• P53
• Rb
p53:
it codes for a regulatory protein that turns off cell division
when the cell is stressed or damaged.
If mutated, runaway cell division
More than half of cancers has a mutated or missing p53
gene
NEOPLASTIC CELLS
Increased
In growth
factor
Increased
In growth
factor
receptors
Increased in
signal
transduction
Increase in
activation of
transcription
How does proto-oncogenes get
activated into oncogenes?
– Enhancer insertion
– Promoter insertion
– translocation
– gene amplification
– point mutation
• Point mutations, insertions or deletions that give
rise to an overactive gene product or lead to an
increase in transcription.
• Gene amplification leading to additional copies of
proto-oncogene
• Chromosomal tranlocation that causes a protooncogene to move to a different chromosomal
site associated with increased expression or to
fuse with another gene to produce a protien that
has oncogenic aactivity.
Viral oncogenes
RNA
Retrovirus:
Produces DNA provirus
which
contain
viral
oncogene (v- onc)
DNA virus:
DNA viruses form stable
association with host cell
genome.
• A Reverse transcriptase ( RT) is
An enzyme used to generate complementary
DNA (c DNA) from an RNA template, a
process termed reverse transcription. It is
mainly associated with retrovirusses.
Products of viral oncogenes
Viral oncogenes
Products
erb-B
Epidermal growth factor (EGF)
ras
GTP binding protein
myc
Nuclear protein modify cell growth
src
Protein tyrosine kinase
sis
Truncated platelet derived growth factor
(PDGF)
Growth factors
Growth factor is a naturally occurring substance
capable of stimulating cellular growth and
differentiation, it is usually protein in nature.
Types of growth factors:
Mechanism of action of growth factors:
Endocrine, Paracrine and Autocrine.
Action of growth factors:
Types of cancer genes
Type of gene
Normal function
Mutated function
Types of proteins
Oncogene
Promotes division
Promotes division abnormal time or
cell type
Growth factors
Tumor
suppressor
gene
Suppresses cell
division
Fails to suppress
division
Checkpoint
molecules
DNA repair
gene mutation
Repair DNA
mutations
Fail to repair DNA
mutations
Enzymes for
mismatch or excision
repair