Molecular Introduction to Cancer Biology Flashcards
What types of genes are p53 and RB?
They are tumour suppressor genes.
What are the common characteristics of cancer cells?
Uncontrolled proliferation
Immortality
Angiogenesis
Metastasis
Where are the cell cycle checkpoints?
R -‘go-no go’ signal, cell requires growth signals to pass this checkpoint
G1 - DNA damage checkpoint, entrace to S is blocked if DNA is damaged
G2 - Is DNA replication complete?
M - Are chromatids properly assembled on the spindle?
What is the importance of the R cell cycle checkpoint?
There is a ‘go-no go’ signal, the cell requires growth signals to pass this checkpoint.
What is the importance of the G1 cell cycle checkpoint?
G1 checkpoint - checks DNA damage, entrace to S is blocked if DNA is damaged.
What is the importance of the G2 cell cycle checkpoint?
G2 checkpoint - The G2 checkpoint checks that DNA replication is complete.
What is the importance of the M cell cycle checkpoint?
M cell cycle checkpoint - Checks that chromatids are properly assembled on the spindle.
What are the roles of mitogenic GFs and TGF-β in the G1 phase of the cell cycle?
Mitogenic GFs tell the cell to divide
TGF-β tell the cell to stop division
How does Rb act upon R point transition?
Unless there are particular signals that feed in Rb the brake upon cell cycle control will not be released.
The clutch of the cell cycle.
Why is Rb a vulnerable point in the cell cycle?
Mutation of Rb removes all control of R point transition.
Proliferation can arise unchecked.
How does Rb regulate cell cycle progression?
It phosphorylates proteins.
This hyperphosphorylation is the trigger that allows the cell cycle to proceed.
What disorder was studied that allowed for identification of Rb?
RB was identified in the study of Retinoblastoma
Rb is mutated in the familial cancer, Retinoblastoma. Cells grow out of the retina and extend into the optic nerve. It is malignant and interocular. Typically occurs in children 2/3 years old. A key symptom is light reflected back from tumour cells.
What is the protein product at the centre of the cell cycle signalling pathway?
pRb
Acts as a negative regulator that blocks pathway transition.
Mutations in Rb are very common in all types of cancer
How does Rb control cell cycle progression?
- At the end of mitosis a protein is dephosphorylated
- In G1 it is then hypOphosphorylated. A single phosphate is put on bu D-CDK4/6 kinase. The cyclin is an effector molecule.
- At the R point the molecule become hypERphosphorylated. Many phosphates are added by E-CDK2 complex which requires the protein to have 1 phosphate already attached.
- The amount of CDK4/6 and cyclin in the cell is increased by mitogen signalling. Thus mitogen signalling increases phosphorylation. Growth factors will signal down through the network and increase the amount of CDK4/6. In early G1 any unphosphorylated pRb is phorphorylated by CDK4/6. In late G1, CDK2 will start hypERphosphorylating to drive the cell cycle through S and G2.
- At endomitosis there is a phosphorylase that takes the phosphate off so the molecule can go round the cell cycle again.
What molecules are involved in the phophorylation of Rb?
Mitogens act on a pathway that increase the levels of cyclin D and CDK4/6. As these proteins increase they form a complex that hypOphosphorylates Rb (adds one phosphate).
Rb is then hypERphosphorylated in late G1 if their is sufficient amounts of the Cyclin E-CDK2 complex present. There is a conformational change in Rb, this changes its interactions with other protein complexes.
The cell can then transfer through the R point and become commited to the rest of the cell cycle.
What transcription factor is attached to unphosphorylated Rb?
E2F
The phosphorylation of pRB causes a conformational change and the release of E2F.
What complex allows for the hyperphosphorylation of pRB?
Cyclin E/CDK2 complex
What causes the conformational change that results in pRB releasing E2F?
The hyperphosphorylation of pRB, facilitated by high levels of Cyclin E/CDK2. E2F can then act as a transcription factor.
What is the role of E2F in the cell cycle?
Unphosphorylated and Hypophophorylated pRb binds to E2F preventing it from finding target genes and switching on transcription.
When pRb becomes hyperphosphorylated there is a conformational change that releases E2F.
E2F can then act as a transcription factor, finding downstream genes and activating them. These target genes are involved in DNA synthesis in S phase.
If there is more active E2F TF there is more E2F produced and also Cyclin E, this leads to more Cyclin E/CDK2 complex building up in a positive feedback loop. This amplifies the signal to drive the cell cycle.
What inhibitors act as tumour suppressor genes on Cyclin E / CDK4/6 complex?
p16INK4A and p16INK4B are inhibitors of Cyclin E / CDK4/6 complex. Acts as a brake on the cell cycle.
If there are mutations in p16 or p15 this prevents the breakage of the Cyclin E / CDK4/6 complex.
What is p21?
p21 acts downstream of p53 and is often triggered when there is DNA damage. Its stops the cell cycle before damaged DNA is replicated.
