(7) Cell Cycle, Apoptosis and Cancer Flashcards
Broad overview of the cell cycle?
- Cell growth and chromosome replication
- Chromosome segregation
- Cell division
What are the stages of the cell cycle?
- The S Phase (Synthesis)
2. The M Phase (Mitosis)
Insert stages of the cell cycle here!!!
Slide 7
The Stages of the cell cycle:
What occurs in MITOSIS (M):
- Nuclear division (mitosis) at the beginning
- Cell division (cytokinesis) at the end
The Stages of the cell cycle:
What occurs in interphase?
(G1): Gap 1 phase; RNA and protein synthesis needed for DNA replication
(S): DNA synthesis
(G2): Gap 2 phase- DNA stability is checked
The Stages of the cell cycle:
What occurs during Go phase?
Occurs during POOR NUTRIENT/enviornmental conditions
–> Cells withdraw from cell cycle
*Also occurs following terminal differentiation in certain tissue types
The Stages of the cell cycle:
What are restriction points/checkpoints for?
A discrete timepoint where “errors” are checked
The Stages of the cell cycle:
___ Restriction point
___ Checkpoints
one restriction point; 3 checkpoints
The Stages of the cell cycle:
What happens if growth factors are limiting?
Growth factors are limiting
The Stages of the cell cycle:
Progression following exit from restriction point (R) is growth factor _________
independent
The Stages of the cell cycle:
G1 checkpoint
Occurs in response to:
DNA Damage
The Stages of the cell cycle:
G2 checkpoint
Purpose?
Verify complete genomic duplication
The Stages of the cell cycle:
Metaphase checkpoint
Purpose?
Ensures chromosomes attached to mitotic spindle
Cell cycle is activated by ______
growth factors
Retinoblastoma (Rb) and Cyclin activity: Describe
Rb and E2F are associated with each other. Cyclin D-CDK4 and Cyclin D-CDK6 can hyperphosphorylate RB to dissociate it from E2F…
Then, E2F can actively transcribe
____________ drives cells from G1 to S phase of the cell cycle
Rb Phosphorylation
Once E2F is actively transcribing, what does it produce?
Cyclin E: cell cycle goes from G1 to S phase
Cyclin A: S phase can occur
Retinoblastoma protein is known as a __________ protein
tumor suppressor
What are activators of cyclin-CDK activity?
-Binding of cyclin to CDK causes only PARTIAL activation
***FULL activation=CDK activating kinase (CAK)
What are inhibitors of Cyclin-CDK activity?
- p27
- WEE1
Cdk-activating kinase (CAK) and the T-Loop
What’s its role?
T-loop is a region of CDK that blocks active site
- T-loop moves out of active site after cyclin binding
- CAK phosphorylates T-loop which FULLY activates enzyme
What specific cyclins help the passage of cells through the restriction point in late G1 phase?
Cyclin D-CDK4
CyclinD-CDK6
What are the methods to regulate Cyclin-Cdk activities?
- Phosphorylation of CDK
- Binding of CKI (p27/WEE1)
- Proteolysis of cyclins
What can make a Cyclin-CDK complex fully active after being hyperphosphorylated?
CDC25 phosphatase
p53 is the…
“Guardian of the genome”
-A transcription factor
p53
In the absence of DNA damage…
MDM2 degrades p53
p53
In the presence of DNA damage…
Activates protein kinases that phosphorylate p53 (*ACTIVATES)
- Increased transcription of p21
- CKI
Extrinsic pathway:
What is the caspase associated?
Procaspase 8 –> Caspase 8
Extrinsic pathway:
AKA?
Death receptor pathway;
triggered by binding of external death ligand
Extrinsic pathway:
What are examples of external death ligands?
Fas ligand, TNFalpha (tumor necrosis factor)
Extrinsic pathway:
What happens after caspase 8 becomes active?
Activates caspases -3, -6, -8
Intrinsic pathway:
AKA?
Mitochondrial pathway
Intrinsic pathway:
What causes it?
Triggered by:
Growth factor withdrawal, DNA damage, cell cycle defects
Intrinsic pathway:
How does it happen?
Cytochrome C released by stressed mitochondria, binds to n
Intrinsic pathway:
How does it happen?
Cytochrome C released by stressed mitochondria
Binds to an adaptor protein (APAF-1)
Leads to Apoptosome
Recruits Caspase 9
Intrinsic pathway:
What can facilitate?
*Proapoptotic
BAX
BAK
p53
Intrinsic pathway:
What can inhibit?
*Antiapoptotic
BCL-2
BCL-xl
How can a proto-oncogene be converted to oncogenes?
3 mechanisms
- Point mutation/deletion
- Gene amplification
- Chromosomal translocation
What is an example of a common oncogene?
HER2 Receptor
OVEREXPRESSED HER2, observed in many breast cancers
What is the major example of a tumor suppressor with a clinical correlation in the lecture?
Retinoblastoma (Rb)
What is the difference b/w sporadic retinoblastoma and hereditary?
Sporadic= RARE, 2 independent mutations of Rb
Hereditary= Mutation/deletion of one copy of RB1, predisposed to be cancerous
What are the functions of tumor suppressors?
- Repress cell cycle progression
- Promote apoptosis
- DNA repair proteins (BRCA)
Name some other tumor suppressors:
- RB1 –> Rb
- TP53–> p53
- PTEN; Phosphatase and tensin homolog
- APC; adenomatous polyposis coli
What is the function of metastasis suppressors?
*Cell adhesion proteins
- Prevent tumor cells from dispersing
- Block loss of contact inhibition
- Inhibit tumor metastasis
T/F
You can get cancer from a single hit of a tumor suppressor gene
FALSE!
You need multiple pathways to fail in order to cause cancer
HPV:
E6 binds to
p53
HPV:
p53 binds to
E6
HPV:
E7 binds to
Rb
HPV
Rb binds to
E7
What does GLEEVEC do?
- Competitive inhibitor of Bcr/c-Abl enzyme which is derived from the philadelphia chromosome 22/9 translocation, which stops the cell cycle
- Anti-cancer
What is the mechanism of Erbitux?
EGF INHIBITOR
