Cell cycle and cancer development Flashcards
What are cyclins?
Cyclins are proteins associated with each stage
of the cell cycle.
They drive the cell cycle by activating or inactivating
signalling pathways at each stage.
Cyclins are activated by cyclin-dependent kinases (CDKs).
What happens during G1/S transition?
Mitogens bind to cell surface receptors and activate
downstream signalling pathways.
Expresses cyclin D and activates CDK4/6.
CDK4/6 phosphorylates Rb.
P-Rb cannot bind to E2F transcription factor, and E2F
is activated.
G1/S genes are transcribed and translated.
Cell passes through G1/S checkpoint.
What happens at the G1/S checkpoint?
p53 is activated by downstream signalling pathways from DNA damage.
Triggers the activation of p21 – a CDK inhibitor.
CDK inhibitor binds to CDKcyclin complex and blocks
progression of cell cycle until DNA is repaired.
p53 also activates the DNA damage response proteins.
What is the role of tumour suppressor genes (TSGs)?
Normally restrict cell division or activate apoptosis.
Loss-of-function mutations leads to uncontrolled cell division.
Examples include:
Cell cycle inhibitors e.g. Rb.
Apoptosis-inducers e.g. p53.
Checkpoint proteins that trigger cell cycle arrest in
presence of DNA damage e.g. p53, BRCA1.
What are oncogenes?
Genes which in certain circumstances can transform a cell into a tumour cell.
Examples include:
Genes involved in embryogenesis.
Growth factor receptors e.g. EGFR.
Downstream signalling proteins in cell growth pathways e.g. HRAS, KRAS.
Chromosomal translocation e.g. BCR-ABL – unregulated high expression of tyrosine kinase activity.
What is EGFR?
Epidermal growth factor receptor (EGFR) is a member of the ErbB family of receptor tyrosine kinases.
Can act as mitogens, growth factors, survival factors.
ErbB RTKs are mutated in many cancers.
Mutations can be kinase-activating or over-expression of EGFR.
How do drugs act on RTKs?
All bind to the tyrosine kinase and block its action e.g.
competitively or allosterically.
Development of resistance to RTK inhibitors by mutations in the cancer cell is a limitation of these drugs.
How do cancer cells deregulate signalling pathways
for uncontrolled growth?
Increased expression of growth signals.
Increased expression of growth factor receptors.
Production of signalling molecules that activate
neighbouring cells in the tumour.
Increased expression of downstream signalling
molecules to bypass the growth signal itself.
Disruption of negative feedback loops.
How do cancer cells avoid tumour suppressor genes?
Cancer cells develop mutations that evade negative
regulators of the cell cycle.
Prototypic examples are:
Rb - central role in cell cycle regulation
p53 - central role in DNA damage and apoptosis
Both have some redundancies, so often associated with mutations other tumour suppressor genes in the pathway.
How do cancer cells resist cell death?
Cancer cells deregulate pathways that block cell death:
Activation of anti-apoptotic proteins or suppression of proapoptotic proteins.
DNA damage sensors blocked.
Overexpression of survival factors or related pathways.
Many cancers have mutated p53 – links into many of these pathways.
What is angiogenesis?
Angiogenesis is required to sustain tumour growth.
Cells in a tumour require nutrients and oxygen, and ability to remove waste products and CO2.
Most common mutations are in angiogenesis signalling - vascular endothelial growth factor A (VEGF-A) and downstream pathway.
