Cell Cycle Flashcards
List the phases of the cell cycle.
Interphase - G1, S, G2 - Growth and replication
Prophase - chromatin condensing
Prometahase - spindles align at centromere
Metaphase - chromosomes align at metaphase plate
Anaphase - pulls chromatids apart to poles
Telophase - poles move and separate
Cytokinesis - cells split via mitosis
What is alternation and completion?
Alternation - cell cycle events always occur in the right order.
Completion - one process must finish before the next one is able to begin.
Describe the 3 cell fusion experiments.
1 - Cells in interphase are fused with cells in mitosis – ALL cells undergo mitosis. Proves alternation.
2 - Cells in G1 fused with cells in S – ALL cells in S phase. Proves alternation.
3 - Cells in S fused with cells in G2 – Cells are in G2 delay until all cells complete S phase. Proves completion, cannot enter mitosis until all cells in G2.
How is the alternation process regulated?
Cyclins and CDKs.
Cyclins are the regulatory subunits for CDKs by binding, causing a conformational change that allows CDK activating kinase to phosphorylate and activate.
CDKs phosphorylate and activate proteins involved in the cell cycle progression.
Draw the Cyclin-CDK graph.
Check
What activates the anaphase promoting complex (APC) and what is its function?
Cyclin B / CDK1 activates APC by phosphorylation. APC is an E3 ligase that targets cyclins for proteasomal degradation.
Also controlled by the spindle tension sensor to stop anaphase starting too early.
What is the function of the anaphase checkpoint (SAC)?
Stops aberrant mitoses, deregulation causes cells with wrong number of chromosomes (aneuploidy).
Explain the G1/S Restriction checkpoint.
Draw
How are cancer cells able to pass through the G1 - R checkpoint in absence of growth factor stimuli by self sufficient growth signals?
Self sufficient growth signals:
- over expression of EGFR/Erb1/2/HER2 TKRs
- oncogenic Ras mutations causing over expression of Cyclin D.
- Overexpression of Cyclin D from gene amplifications.
- Amplifications of CDK4/6.
How are cancer cells able to pass through the G1 - R checkpoint in absence of growth factor stimuli by insensitivity to anti-growth signals?
Insensitivity to anti-growth signals.
- Loss of TS genes that control cell cycle (p14ARF for p53 control, p16INK4A for Rb control)
- Loss of Rb controlling the G1-R checkpoint
- TGFB1 signalling: TGFB1 binds to TGFB receptors, activates SMAD TF cascade, increases CDK inhibitor expression. In cancers, SMAD genes lost, CDKi expression decreased.
What is the function of p53 and how is it mutated in cancers?
DNA damage, hypoxia, oncogenic stimuli, senescence causes activation of p53 - leads to cell cycle arrest (CDKi) and apoptosis.
p53 binds DNA as a tetramer, only one monomer needs to be mutated for a loss of function.
How is p53 activity regulated?
Mdm2 is the main p53 regulator in cells, directs its ubiquitination and degradation.
Oncogenic Ras decreases levels of p14ARF (Mdm2 inhibitor) to increase the degradation of p53.
What are the 3 mechanisms of p53 inactivation in cancers?
- p53 point mutation / gene loss
- loss of p14ARF expression
- Mdm2 gene amplification
Example of how next generation cancer therapeutics target oncogenes/TS genes.
CDK inhibitors - Pablociclib = drug that helps advanced breast cancer
