4. molecular basis of cancer dr. sinhasan, mdzah
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Transcript of 4. molecular basis of cancer dr. sinhasan, mdzah
Acquired (Environmental)
DNA damaging agents:
* Chemicals
* Radiation
* Virus
Normal Cell
DNA damage
Mutations in the genome
of somatic cells
Alterations of genes
that regulate Apoptosis
Activation of growth
promoting oncogenes Inactivation of
cancer suppressor
genes
Successful
DNA repair
Failure of DNA repair
Expression of altered gene products
and loss of regulatory gene products Clonal expansion
Additional mutations
Heterogeneity.
Inherited Mutations:
-DNA repair
-Cell growth
- Apoptosis
TUMOURS ARE MONOCLONAL
•All the tumor cells derived from single mutated cell.
•All the cell in one tumor will express the same genetic
change.
•Tumor is formed by –the Clonal expansion of single
precursor cell that has incurred genetic damage.
1. Self-sufficiency in growth signals
2. Insensitivity to growth-inhibitory signals
3. Evasion of apoptosis
4. Limitless replicative potential
5. Sustained angiogenesis
6. Ability to invade and metastasis
7. Escape from immunity and rejection.
Orderly progression of cells through the various stages of
cell cycle is orchestrated by cyclins and cyclin dependent
kinases (CDKs) and by their inhibitors.
By phosphorylation CDK’s will drive the cell cycle—cells will
proceed to the next stage of proliferation.
CDK’s are normally in inactive form.
They become activated by phosphorylation after binding to
the family of proteins called Cyclins.
They are inactivated by ubiquitin - proteosome pathway after
their action.
Cyclins: main function is to activate the CDK’s.
E.g., cyclins D, E, A & B
CDK’s: cdk 4, cdk 2, cdk 1.
Phosphorylation of RB gene is ON-OFF switch of cell
cycle.
In hypophosphorylated state, RB gene prevents cells
from replication by forming tight, inactive complex with
transcription factor E2F.
Phosphorylation of RB gene eliminates main barrier to
cell cycle progression and promotes cell replication.
It is “point of no return” in the cell cycle
Before cell makes its final commitment to replicate, the
G1/S check point checks for DNA damage.
If DNA damage is present, the cell repair machineries will
repair it and arrests the cell cycle.
They provide some time for DNA repair; irreversible
damage—Apoptosis—Cell death.
Monitors the completion of DNA replication and checks
whether cell can safely initiate mitosis.
Defect in this checkpoint can give rise to various
chromosomal abnormalities.
To function properly, checkpoints take the help of many
‘sensors’—which will senses the damage.
Protooncogenes are physiological regulators of the cell cycle—control cell proliferation and differentiation.
Oncogenes –are characterized by ability to promote cell growth in the absence of normal mitogenic signals.
Oncoproteins –are products of oncogenes: the production of which is independent of growth factors.
Definitions:
1. PROTO-ONCOGENES,
[ ONCOGENES ]
2. TUMOUR SUPPRESSOR GENES,
3. GENES THAT REGULATE APOPTOSIS,
4. DNA REPAIR GENES.
GENES AFFECTED IN CANCER:
Promote autonomous cell growth,
Cell growth in the absence of mitogenic
signals,
Their products – oncoproteins,
VARMUS & BISHOP: 1989: Nobel prize;
ACUTE TRANSFORMING RETROVIRUSES
Oncogenes And Cancer:
V - oncVIRAL ONCOGENE
Animals TUMOURS
Molecular analysis of viral genome
-
PDGF - beta chain :
== Astrocytoma
== Osteosarcoma,
FGF : == Stomach cancer
== Bladder cancer
== Breast cancer,
== Melanoma,
Can be:
Overexpressed by tumor cells : E.g., as in case of
Astrocytomas and Osteosarcomas—PDGF is
Overexpressed.
Amplification : e.g., in case of Stomach and Breast Ca—
FGF is amplified.
“Many cancer cells develop
growth self-sufficiency
by acquiring the ability to synthesize
the same growth factors
to which they are responsive”!
Overexpression of growth factor genes.
Proto-oncogenes Oncogenes
… Insertional mutagenesis,
… Point mutations,
… Chromosomal translocations,
… Gene amplification
“Extensive cell proliferation
increases the chance of
spontaneous or induced mutation
in cell population”
“Any cell----which is dividing rapidly…..,is susceptible for
developing point mutations..hence and malignancies ”