Tumour pathology 4 Flashcards
Describe the G1 phase
- Cell increases in size
- G1 checkpoint control ensures cell is ready for DNA synthesis
Describe the S (interphase) phase
DNA replication occurs
Describe the G2 phase
- Cell continues to grow
- G2 checkpoint ensures cell is ready for mitosis
Describe M (mitosis) phase
- Cell division
- Metaphase checkpoint ensures cell is ready to complete division
Mechanisms of cell cycle control
- Quality control
- Checkpoints
- External factors
- Intrinsic factors
Describe quality control
Ensures genetic fidelity in daughter cells
- Each cells receives full chromosome complement
- Mutations in DNA sequences not passed on
Describe checkpoints
Monitor and regulate progress
Describe external factors
Hormones, growth factors, cytokines
Describe intrinsic factors
Critical checkpoints - restriction point
Describe the G0 (quiescent) phase
Resting phase; cell has left cycle and stopped dividing
Cells that don’t divide stay in G0 - cardiac and neuronal cells
What checkpoint is used if cell is too small?
G1 and G2
What checkpoint is used if nutrient supply is low?
G1
What checkpoint is used if external stimulus is lacking/
G1
What checkpoint is used if DNA not replicated?
S
What checkpoint is used if DNA damage is detected?
G1 and G2
What checkpoint is used if there is chromosome misalignment?
M
What are cyclin dependent kinases (CDKs)?
Catalytic subunits that are present in all cells in their inactive form - they act as checkpoint
Different CDKs at each phase
What are cyclins?
- Regulatory sub-units that also act as checkpoints
- Different at each phase
- They accumulate then are destroyed as cycle progresses
What happened when CDKs and cyclins bind?
- Active CDK/cyclin complexes phosphorylate target proteins
- Phosphorylation results in activation/inactivation of that substrate
Checkpoint mechanism at G1
CDK-4 and cyclin D bind and phosphorylate Rb (inactivating it) which blocks it from inhibiting DNA replication (loses affinity for E2F transcription factor) allowing cell cycle to continue
Describe regulation of CDK activity
CDK inhibitors (CKIs) like INK4As family which bind to CDK4 and 6 and prevents their cyclin proteins from binding -CIP/KIP family
Without CDK-4 and cyclin D - pRb will bind to E2F and stop the cell cycle
What is pRb function?
Targets E2F transcription factor - active pRb inactivates E2F which prevents DNA replication (stops cell cycle)
Hypophosphorylated - active
Phosphorylated - inactive (loses affinity for E2F)
What is carcinogenesis?
Genetic disease caused by a mutation that disrupts the normal balance between proliferation and apoptosis
What does uncontrolled proliferation lead to?
Tumours
What gene mutations lead to loss of proliferation control?
Genes regulating cell division, apoptosis and DNA repair
What two bases in DNA are damaged by chemical and radiation carcinogens?
Purine and pyrimidine
What two pathways are frequently disrupted in cancer?
- Cyclin D-pRb-E2F pathway
- p53 pathway
p53 function
Levels increase in damaged cells
- Induced cycle arrest at G1
- Facilitates DNA repair
- Apoptosis in severe damage
p53 in cancer
Mutated p53 does not arrest at G1 or repair damaged DNA so daughter cells inherit mutations
Daughter cells proliferate and form malignant neoplasms
