Cell Cycle and Checkpoints of Cell Division Flashcards
What are the four reasons to produce new cells?
- Duplicate DNA and segregate copies into daughter cells
- Replace old cells
- Repair injury
- Build new tissue
What typically occurs with cell cycle regulation? What happens if there is failure of cell cycle regulation?
Normally, if there is damage in a mother cell, the DNA repair pathway is signaled and the cell cycle will be stopped (cell division stops until DNA is repaired)
- If there is cell cycle regulation failure, some cells will undergo apoptosis but others will continue with the cell cycle and ultimately produce mutant daughter cells from the damaged mother cell
What is the role of the BRCA gene? What is the result of a mutation in the BRCA gene?
BRCA gene produces proteins involved in DNA repair
- If there is a mutation in the BRCA gene, the production of other genes that perform DNA repair will not occur, resulting in increased risk for breast or ovarian cancer
What are the four phases of the cell cycle? Describe each
- G1: duplication - all non-chromosomal cellular contents are duplicated
- S: synthesis/replication - each of the 46 chromosomes are duplicated
- G2: proofread/repair - cell double checks the duplicated chromosomes for any errors and repairs are made, if needed
- Mitosis: division - duplicated chromosomal DNA condenses into mitotic chromosomes
What are the five stages of mitosis?
- Prophase
- Prometaphase
- Metaphase
- Anaphase
- Telophase
What is the final phase of the cell cycle (hint: sort of part of mitosis)? What happens in this phase?
Cytokinesis: the mitotic cells are divided into two daughter cells
How does the cell cycle begin? What does this step result in?
Mitogen (ligand) binds to their receptors on the cell surface, initiating a phosphorylation cascade
What gene and cascade are typically involved with the cell cycle initiation?
Ras gene and the MAP Kinase cascade
What are two results of the MAP Kinase cascade?
- MAP Kinase increases synthesis and activity of the MYC transcription factor
- MYC increases the expression of the cyclin D
What is required for the progression through checkpoints of the cell cycle? How is this process achieved (hint: complex)?
Progression through checkpoints requires phosphorylation of key proteins
- Phosphorylation is achieved by cyclin-CDK complexes
What are cyclins, and how are they regulated? How is cyclin synthesis regulated, and what is the one exception?
Cyclins are the regulatory subunit that bind to CDKs, ensuring that only proteins relevant to a specific cell cycle phase are phosphorylated
- Besides cyclin D, cyclin synthesis is initiated by preceding phase’s signaling event
How is cyclin D synthesis regulated?
Cyclin D is the only cyclin that’s synthesis is dependent upon
What does CDK stand for? How are they activated, and what is their role in the cell cycle when active?
Cyclin-dependent kinases (CDKs) are the “master switches” that regulate each phase of the cell cycle
- Always present in cells, but only active when bound to cyclin
What is always the first active cyclin-CDK complex of the cell cycle?
Cyclin D-CDK4/CDK6
What are the cyclin-CDK complexes for each phase (hint: there are 5)
- G1 (early): cyclin D-CDK4/CDK6
- G1 (late): cyclin E-CDK 2
- G1/S: cyclin A-CDK 2
- S/G2: cyclin A-CDK 1
- M: cyclin B-CDK 1
What are the three major cell cycle checkpoints and at which phase(s) do they occur?
- Restriction (R) checkpoint in G1 phase
- G2-M checkpoint at the G2 and M phase
- M phase checkpoint at end of M phase
What are the two pathways that can occur at the R checkpoint?
- In the presence of appropriate growth factors, cells pass the R checkpoint to enter S phase
- If appropriate growth factors are not present, cell stops and enters G0
What is the G0 phase?
G0 is the “dormant” phase where cells are metabolically active but cease growth and have reduced rates of protein synthesis
What two cyclin-CDK complexes must be present in order to pass through the R checkpoint?
CyclinD-CDK4/CDK6 and CyclinE-CDK2 must both be present in order for cells to pass through the R checkpoint
What two proteins are involved in the R checkpoint? When these two proteins are bound to each other, what is inhibited?
Rb protein and E2F protein
- When complexed together, the transcription of S phase genes cannot occur
What is hypophosphorylation? What is hyperphosphorylation? What two residues are phosphorylated on the Rb protein and what does this result in?
Serine and threonine residues on the Rb protein are phosphorylated, inactivating the protein
- Hypophosphorylation of Rb protein allows for partial activation of E2F (some transcription of S phase genes)
- Hyperphosphorylation of Rb protein allows for complete activation of E2F (free to transcribe S phase genes)
What is the second checkpoint of the cell cycle? What is this checkpoint dependent on?
G2-M checkpoint between the G2 phase and M phase
- Depends on completion of DNA replication
What cyclin-CDK complex does the second checkpoint depend on?
Activation of the cyclin B-CDK1 complex
What is the third checkpoint of the cell cycle, and what is an alternative name for this checkpoint? What is this checkpoint dependent on?
M phase checkpoint, or Spindle Assembly checkpoint, at end of M phase
- Depends on the proper alignment of mitotic chromosomes in metaphase
What cyclin-CDK complex does the third checkpoint depend on? Is this complex active or inactive?
Deactivation of the cyclin B-CDK1 complex
If DNA damage is present, how does the cell stop the cell cycle?
CDK inhibitors (CDKIs)
What is the role of CDKIs in inhibiting the cell cycle?
CDKIs can bind to the cyclin-CDK complex in any phase in order to inhibit the activity of the kinase
What are the two types of CDKIs? What is the function of each and what protein does each involve?
- INK4: CDK4 or CDK6 inhibitor that includes the protein p16
- CIP/WAF1: CDK interacting protein that includes the protein p21
When is the p16 protein induced? When is the p21 protein induced?
- p16 protein is induced during times of environmental stress
- p21 protein is induced only under conditions of DNA damage
What protein regulates p21 protein production? Describe this process in five steps
p21 production is regulated by the p53 protein
- Increased p53 protein
- p53 is activated by phosphorylation
- p53 binds to promoter region of p21 gene
- Increased production of p21 mRNA and proteins
- p21 can bind to cyclin-CDK complexes and inhibit their activity
What is the one cyclin-CDK complex that cannot be regulated by p21? Why is this?
CyclinD-CDK4/CDK6
- It is inhibited by the p16 protein
How does a loss-of-function mutation of p53 affect cell cycle regulation?
p53 is not functioning properly leading to p21 not being produced and cyclin-CDK complexes being always active
How does a loss-of-function mutation of p21 affect cell cycle regulation?
p21 cannot inhibit cyclin-CDK complexes (always active)
How does mitogen-independent synthesis of cyclinD affect cell cycle regulation?
Production of cyclinD is always on
What is an example of a mutation involving mitogen-independent synthesis of cyclinD?
Ras gene mutation
How does a loss-of-function mutation of p16 affect cell cycle regulation?
CDK4/CDK6 always active (not inhibited)
How does a loss-of-function mutation of Rb protein affect cell cycle regulation?
Rb will not be complexed with E2F so E2F is free to constantly transcribe S phase genes
