NEOPLSIA 1
ONCOGENESIS
Dr. D. Madziwa
November 5th 2019
Cell Cycle
post-replication checkpoint
pre-replication checkpoint
Control of Normal Cell Proliferation and Tissue
Growth
• Cell population size depends on rate of proliferation differentiation and
death by apoptosis.
»
» Differentiation
• Proliferation Baseline Stem Cells
» Cell Population
» Cell Death
» (Apoptosis)
# Cell population dynamics in Healing via proliferation
3
Control of normal cell
growth
• Cell cycle and proliferation:
• Cell cycle with 4 phases:
G1 = presynthetic
S = DNA synthesis
G2 = premitotic
M = mitotic
Three types of cells
• Continuously dividing cells -labile
(surface epithelia, glands)
• Quiescent (or stable) cells
(mesenchymal cells, liver cells)
• Nondividing (permanent) cells
(neurons)
Cell cycle and the regulation
of cell division
Controlling of the different phases of the
cell cycle and of division by:
1. Cyclins A, B, E (proteins)
2. So called checkpoints which monitor
whether certain molecular events are
completed.
Regulation of Cell Cycle
Molecular basis of cancer
1. Growth promoting genes
2. Tumour suppressor genes
3. Genes regulating apoptosis
4. DNA repair genes
ONCOGENES
Mode of action
– Overexpression
• Abnormal gene product
– Amplification
• Abnormal amount of normal gene product (mutation in
regulatory part of gene
– Point mutation
– Translocation
Chromosomal Alterations in Carcinogenesis
CML
Five classes
• 1.Growth factors
• 2. Growth factor receptors
• 3. Signal transduction proteins
• 4. Nuclear regulatory proteins
• 5. Cell cycle regulators
Oncogenes
1. Genes for growth factors and their receptors
• PDGF codes for platelet derived growth factor,
involved in glioma
• erb-B codes for the receptor of epidermal growth
factor (glioblastoma, breast cancer)
• erb-B2 also called HER-2, codes for growth factor
receptor
• RET codes for a growth factor receptor, involved in
thyroid cancer
Oncogenes
2. Genes for cytoplasmic relays in stimulatory
signaling pathways
• Ki-ras involved in lung, ovarian, colon and
pancreatic cancer
• N-ras involved in leukaemias
Oncogenes
3. Genes for other kinds of molecules
• Bcl-2 codes for a protein that normally blocks cell
suicide, involved in follicular B cell lymphoma
• Bcl-1 also called PRAD1, codes for cyclin D1, a
stimulatory protein of the cell cycle clock,
involved in breast, head and neck cancer
• MDM2 codes for an antagonist of the p53 tumour
suppressor protein, involved in sarcomas and
other cancers
Genes for transcription factors that activate
growth promoting genes
•c-myc involved in leukaemias, breast, stomach and
lung cancer
•N-myc involved in
neuroblastomas and glioblastomas
•L-myc involved in lung cancer
Oncogenic products
Cellular oncogenes encode polypeptides involved in transduction of
signals related to cell growth and differentiation by:
1. Encoding growth factors (c-cis, transforming growth factor alpha
and beta
2. Encoding membrane bound receptors for extra-cellular growth
factors (c-fms, c-erb-b)
3. Encoding polypeptides associated with either the cytoplasm or the
inner surface of the plasma membrane that transduce signals
between membrane and cytoplasmic proteins (c-src, c-ras,c-
ab)
4. Encoding cytoplasmic receptors for hormones, such as steroids
and thyroid hormones (c-erb-a)
5. Encoding nuclear polypeptides that bind specifically to regulatory
DNA regions and presumably modulate transcription and
replication (c-fos, c-myc, c-myb, c-jun)
Growth Factors
• Epidermal growth factor (EGF) family
• Transforming growth factor- (TGF)
• Platelet derived growth factor (PDGF)
• Fibroblast growth factor (FGF)
– Basic
– Acidic
• Transforming growth factor- (TGF-) family
– Bone morphogenic proteins
– Activins, others
• Vascular endothelial growth factor (VEGF)
• Angiopoetins (Ang)
• Insulin-like growth factors (IGF)
Tumour suppressor genes
• Genes that block normal cell differentiation
• Recessive genes – both alleles have to be
mutated to be expressed
– 2 hit hypothesis (Knudson’s hypothesis)
– Loss of heterozygosity
Tumour suppressor genes
1. Genes for proteins in the cytoplasm
• APC involved in stomach and colon cancers
• NF-1 codes for a protein that inhibits a stimulatory
(Ras) protein, involved in neurofibroma and
phaeochromocytoma and myeloid leukaemia
• NF-2 involved in meningeoma and ependymoma
and schwannoma
Tumour suppressor genes
2. Genes for proteins in the nucleus
• RB codes for the pRB protein, a master brake of the
cell cycle, involved in retinoblastoma, bone,
cervical cancer, breast
• p53 codes for the p53 protein, which can halt cell
division and induce abnormal cells to kill
themselves, involved in a wide range of
cancers including Cervical cancer
• WT1 involved in Wilms`tumour of the kidney
Tumour suppressor genes
3. Genes for proteins for which the cellular location is
not yet clear
• BRCA1 involved in breast and ovarian cancer
• BRCA2 involved in breast cancer
• VHL involved in renal cancer
Genes regulating apoptosis
• B-cl 2 gene
– Inhibits apoptosis (follicular lymphoma)
DNA Repair Genes
• Xeroderma pigmentosum
• Bloom syndrome
• Ataxia telangiectasia
• Fanconi anaemia
After Transformation of the cell by
Mutation
Translocation
Amplification
Over- expression……………… the cancer
story begins!
• END
