Cell replication Flashcards
What is the cell cycle?
- cell growth and chromosome replication
- chromosome segregation
- cell division
What is the orderly sequence of events in which a cells duplicates?
- duplication
- division
- coordination
Different cells divide at different rates
fastest: embryonic and yeast cells
What does the rate of division depend on?
- the type of cell
- complexity of system
- necessity for renewal
- state of differentiation (some cells never divide)
- tumour cells
What are the phases of the cell cycle?
G1 phase
S phase
G2 phase
M phase (mitosis)
What does G phase stand for?
gap
What is the interphase?
G1 + S + G2
What is G0?
quiescent phase
What happens in the absence of stimulus to cells?
they go into G0
Which cells arent dormant, but are non-dividing?
neurons
skeletal muscle
hepatocytes
How does the cell decide if it can enter the cycle?
Monitoring external environment: - nutriets
- growth factors
When does a cell pause?
DNA repair
undergo apoptosis
Why do cells ever leave G0?
signalling cascades
What are the signalling cascades?
- response to extracellular factors (growth factors stimulate entry from G0 into the G1 phase)
- signal amplification
- signal integration/ modulation by other pathways
- Ras/ Raf /MEK/ ERK (kinases- enzymes)
What do the kinase enzymes do in the cell cycle?
- protein synthesis increased
- protein degradation decreased
- -> overall net growth of the cell
What is c-Myc ?
transcription factor
drives the production of specific cell cycle genes
induced the expression of Cyclin D which drives entry into S phase
What do growth factor signalling pathways induce?
the expression of c-Myc
- c-Myc promotes G0 to G1 transition
- c-Myc is an oncogene - overexpressed in many tumours
What is the key role of Cyclic dependant kinases (Cdks)?
phosphorylation + dephosphorylation
- key signaling events
- serine/ threonine/ tyrosine
What else do Cdks allow?
exquisite control of events:
- cdks present in proliferating cells
- BUT only active when a cyclin is bound
Why are they called cyclins?
bc their concs within the cell fluctuate
What cyclin is active during mitosis?
Cdk complex
What is the pathway of cell cycle entry?
growth factor –>
C-Myc –>
Cyclin D –>
cyclin D/ Cdk 4/ 6 complex
What are the checkpoints that can arrest the cell cycle?
G1: - damaged DNA
- unfavourable extracellular environment
S: damaged or incompletely replicated DNA
G2: damaged or incompletely replicated DNA
M: chromosome improperly attached to mitotic spindle
What are protein kinase cascades?
Kinases activate a molecule by phosphorylation
phosphorylation of one kinase then allows it to phosphorylate another kinase and a third kinase and so on
What do protein kinase cascades lead to?
- signal amplification
- diversification
- opportunity for regulation
What are phosphatases?
they reverse phosphorylation
Where are cyclin-dependent kinases present?
Cdk1, Cdk2, Cdk4, Cdk6
in proliferating cells throughout the cell cycle
How is the activity of Cdk’s regulated?
- interaction with cyclins
- phosphorylation
Cyclins?
CyclinA, CyclinB, CyclinD, CyclinE
transiently expressed at specific points in the cell cycle
- regulated at level of expression
- synthesised, then degraded
What drives the cell cycle forwards?
Positive feedback
What drives the entry to the S phase?
active S-Cdk
What drives the entry to the M phase?
active M-Cdk
What are the 3 steps required to activate the cdk?
- phosphorylation
- dephosphorylation
- binding of the cyclin (s or M)
How are cyclins turned off?
by ubiqutination (post-it notes- destroy me) and then destruction
When cyclins become sequentially active what do they stimulate?
synthesis of genes requires for the next phase
What is a retinoblastoma?
- a molecular “brake”
- if its missing or inactive –> issues of cell cycle progression
- a tumour suppressor
abundant in all nucleated cells
What does a growth factor do?
drives cell proliferation
What does a retinoblastoma (Rb) act as?
a brake on cell proliferation
What happens when TFs are bound to the retinoblastoma?
Tfs cannot turn of genes needed for cell cycle progresion:
eg DNA polymerase
thymidine kinase
What does the prolyphertion of Rb release?
the brake in a prolypherating cell
- Activation of intracellular signaling leads to production of G1-Cdk and G1/S–Cdk complexes
- can phosphorylate Rb inducing the inactivation of Rb and release of the TF.
- Target genes such as DNA polymerase and thymidine kinase can now activated.
What do E2F family members regulate?
the expression of several genes need for cell cycle progression
What does p53 do?
arrests cells with damaged DNA in G1
What happens in absence of DNA damage?
p53 is degraded in proteasomes
p53 also induces the production of the Cdk inhibitor p21
What happens if there is DNA damage?
- stable, activated p53
- active p53 binds to regulatory region of p21 Gene
- transcription –> p21 mRNA
What are p21 family members?
inhibitors of cyclin: Cdk complexes
What are the oncogenes?
- EGFR/HER2 mutationally activated of over expressed in breast cancers
Herceptin antibody for the treatment of HER2+ metastatic breast cancer - Ras mutationally activated in many cancers
- Cyclin D1 overexpressed in 50% of breast cancers
- C-Myc
overexpressed in many tumours
What are tumour suppressors?
- Rb
loss of function mutations in 80% of small cell lung cancers - p53
loss of function mutations inover 50% of all human cancers
