Cell Proliferation/apoptosis Flashcards
describe how cell proliferation occurs?
- growth factors bind to their cytokine receptors
e.g. EGF/ PDGF - activated intracellular signalling
- change in gene transcription
e.g. up/down-regulation of gene transcription - knock-on effects on DNA replication, cell cycle, mitosis etc.
how can cell proliferation drive cancer progression?
down-regulation of cytokine signalling to initiate/stop gene transcription
what are proto-oncogenes?
normal genes that control proliferation/growth that can become oncogenes due to mutations/increased expression
what are some examples of oncogenes/tumour-inducing agents?
- Gene amplification/over expression: HER2 in breast cancer
- Translocations resulting in hybrid oncogene: BCR-ABL in leukemia
- Missense mutations resulting in constitutively active protein: EGFR in lung cancer, B- RAF in melanoma
describe tumour cells compared to normal cells, in terms of genes.
increase no. of proto-oncogenes
increase gene transcribed
increase gene expression
what receptors do growth factors bind to?
mainly tyrosine kinase receptors
Tyr R
describe Tyr R ?
dimer receptor
what happens when growth factors bind to the Tyr R ?
becomes phosphorylated
causes…
- conformational change
- dimerisation
- activation of tyrosine kinase activity
how can additional receptors bind to Tyr R?
Tyr R is activated and phosphorylated
phosphorylated residues allow various cytoplasmic receptors to join
what are some examples of Tyr R?
PGDF receptor
EGF receptor
Insulin
IGF receptor (insulin-like GF)
what are some examples of growth factors?
platelet-derived growth factors
epidermal growth factors
insulin
insulin-like growth factors
transforming growth factors (TGF-a and TGF-b)
what are some examples of receptors that bind to Tyr R?
RAS pathway
serine/threonine kinase cascades
P.I./lipid signalling pathway
other tyrosine kinases
phospholipase Cy
which receptors that bind to Tyr R drive gene proliferation?
RAS pathway
serine/threonine kinase cascades
other tyrosine kinases
what happens to Tyr R in cancerous tumour?
- amino acid changes/partial deletion
= change tyr activity
= loss of ‘receptor domain’
= GF independent signalling - gene amplification/over-expression
- increased expression of normal receptors
- overexpression of aberrant receptors
what is HER2?
an epidermal growth factor receptor (EGFR)
amplifaction/duplication of HER2 gene in breast cancer
what is BCR-ABL?
a fusion kinase = BCR- ABL increases cell proliferation
- BCR = promotes cell survival
- tyr kinase
- GTP regulator - ABL = promotes cell survival
- cytoplasmic Tyr Kinase
what happens when BCR and ABL genes fuse?
BCR loses GTP regulation
ABL loses inhibitory domain which inactivates ABL
= INCREASES BLOOD CELL PROLIFERATION = leukemia
what genes are apart of the RAS family?
h-ras
k-ras
n-ras
why is the RAS family important?
Most commonly mutated oncogene
what is a common oncogenic mutation in the RAS cycle?
reduced GTPase-activating proteins = no inactivation of RAS = increased cell proliferation due to constant RAS signalling
what does activated RAS do?
phosphorylated MEK which phosphorylates ERK = phosphorylates to activated transcription factors
where is B-RAF mutations common?
melanoma (80%)
lung
colorectal cancers
where do B-RAF mutations occur?
RAS cycle
what is cell apoptosis?
programmed cell death,
allows elimination of damaged cells
