Cell Proliferation II Flashcards
Transcription Factor (3)
- proteins which control gene expression
- activated by proliferative signal
- encode genes that result in synthesis of proteins required to activate and control cell division
Name 3 cell cycle regulators (3)
- cyclins
- cyclin dependent kinases (Cdk)
- Cdk inhibitors (CKI)
What do cyclin-Cdk complexes possess?
Kinase activity
How do cyclin-Cdk complexes form?
by Cdk-activating kinase (CAK)
How do cyclin-Cdk complexes become active?
After Cyclin binds to Cdk,
Cdk-activating kinase (CAK) phosphorylates Cdk
Name the 4 types of cyclin (4)
D, E, A, B
What does Cyclin D bind to?
What is the complex that forms?
What is the function of this complex?
- Cdk 4/6
- D-Cdk 4/6
- To pass the R-point at G1/S boundary
What do Cyclins E and A bind to?
What are the complexes that form?
What is the function of these complexes?
- Cdk2
- E-Cdk2 and A-Cdk2
- To initiate DNA replication in early S phase
What does Cyclin B bind to?
What is the complex that forms?
What is the function of this complex?
- Cdk1
- B-Cdk1
- Transition from G2 to M phase
Chain of Cdk activation (4)
1) Cyclin D synthesised to active Cdk 4/6, in order to pass R-point
2) Cyclin E levels increase and activates Cdk2
3) E-Cdk2 activates A-Cdk2, which is required for DNA replications in S-phase
4) A-Cdk2 activates B-Cdk1 to allow cells to progress to M phase
What is the checkpoint in G1?
Restriction point (R-point)
What is the R-point controlled by?
Retinoblastoma protein (Rb)
What is E2F?
Transcription factor for cell cycle advancement
What is the function of Rb protein?
inhibition of E2F to prevent cell cycle advancement
How does Rb inhibit the action of E2F?
- hypo-phosphorylated Rb is bound to E2F
- preventing E2F to express genes for cell cycle advancement
How does Rb become inactivated? (3)
- hyper-phosphorylation of Rb
- releases E2F
- E2F can now express genes
How does mitogenic signalling allow passing of R-point? (7)
1) Mitogenic signalling activates TFs such as AP-1
2) AP-1 binds to DNA and codes for cyclin D mRNA
3) Cyclin D mRNA translated to synthesise cyclin D
4) Cyclin D binds and activates Cdk 4/6
5) D-Cdk 4/6 phosphorylates Rb, which inactivates Rb and causes it to release its inhibition of E2F
6) E2F is now activated and induces gene expression
7) Cyclin E-Cdk2 hyper-phosphorylates Rb and inactivates it
Function of Cdk inhibitors (CKIs)
bind to cyclin-Cdk complexes and block their action
2 classes of CKIs
- INK4 (inhibits Cdk4)
- CIP/KIP (inhibits Cdk1/2)
Target and Function of:
p16*INK4
(2)
- D-Cdk4/6
- prevents passage of R-point
Target and Function of:
p21*CIP
(2)
- E-Cdk2 and B-Cdk1
- causes cell cycle arrest
What happens in S-phase? (3)
- cells replicate DNA
- cells synthesis chromatin for packaging of DNA into chromosomes
- cyclin A-Cdk2 triggers events resulting in DNA replication
What happens in G2 phase? (3)
- G2 is used to delay commitment of entering mitosis
- to grow in size and check if DNA is faultless
- cyclin B-Cdk1 is formed to allow cells to progress to M-phase
M-phase:
Prophase and Metaphase (5)
Cyclin B-Cdk1 phosphorylates proteins which results in:
- condensing of DNA
- formation of mitotic spindle
- breakdown of nuclear envelope
Chromosome segregation requires correct attachment of sister chromatids to the spindle
M-phase:
Metaphase (3)
- after attachment of sister chromatids to the spindle, chromosomes are tugged between the 2 poles, resulting in them moving to spindle equator
- unattached kinetochores to the spindle are detected by spindle assembly checkpoint which blocks entry to anaphase
- incorrect kinetochore attachment requires correction which causes chromosomes to lag in the spindle
M-phase:
Anaphase and Telophase (4)
Separation of chromatids:
- the pull on kinetochores by the spindle is resisted by the cohesion of the chromatids
- chromatids are connected by cohesin proteins
- cyclin B-Cdk1 triggers the steps to cause breakdown of cohesin
Upon mitogenic signalling, for each of the four phases of the cell cycle, name a main step or a control point and the relevant cell cycle regulator/protein.
G1: pass the R-point
- cyclin D-Cdk 4/6 deactivating Rb
S: DNA replication
- mediated by cyclin E-Cdk2 and A-Cdk2
G2: G2/M control point
- by the action of cyclin B-Cdk1
M: mitotic spindle forms
- by the action of cyclin B-Cdk1
How does cell respond if DNA is damaged? (5)
1) Cells detect DNA damage and activates p53
2) p53 acts as a tumour suppressor and as a transcription factor
3) p53 causes expression of Cdk inhibitors (p21*CIP) halting the cell cycle
4) p53 also causes expression of DNA repair enzymes
5) p53 also expresses apoptotic proteins
Describe how Capsases cause Apoptosis (4)
1) Capsases cleave proteins of the cytoskeleton, causing small blebs to form as membrane bulges out
2) Nucleus breaks apart and DNA breaks into small pieces
3) The cell breaks into several apoptotic bodies
4) The apoptotic bodies end up being cleared by macrophages through phagocytosis
