2: Cell replication Flashcards
Rate of division in embryonic cells
fast (compared to adult cells)
Rate of division in low complexity cells
fast (compared to high complexity)
Rate of division in high turnover cells
fast
e.g intestinal epithelial
Rate of division in terminally differentiated cells
e.g neurones
dont divide
Rate of division in tumour cells
fast
Cell cycle
G1
S
G2
(interphase)
Mitotic phase
Stages of interphase
G0- cell cycle machinery dismantled, not dormant, but non dividing
G1- decision point
S- synthesis of DNA/protein (organelles)
G2- decision point
M-phase
nuclear division
cell division (cytokinesis)
2 outcomes of impaired cell cycle
cell cycle arrest
programmed cell death
Cell cycle arrest
at check points (G1 and spindle checkpoint)
can be temporary (e.g following DNA repair)
Programmed cell death occurs when
DNA damage too great that cannot be repaired
Chromosomal abnormalities
Toxic agents
How do cells enter the G1 phase
Signalling cascade :
response to extracellular factors
Growth factors stimulate entry from G0 into G1
signal amplification
signal integration/ modulation by other pathways
Process of entering into G1 phase
GF signalling pathways induces expression of c-Myc
c-Myc promotes G0 to G1 transition
c-Myc is
c-Myc is an oncogene - overexpressed in many tumours
c-Myc - transcription factor -stimulates expression of cell cycle genes
What gives timing and direction to cell cycle
CDK activity
what cyclin-dependent kinases are involved in the cell cycle
Cdk1, Cdk2, Cdk4, Cdk6
Where are CDKs present
in proliferating cells throughout cell cycle
CDK activity is regulated by
- interaction with cyclins
-phosphorylation
What cyclins are involved in the cell cycle
Cyclin A,B,D,E
When are cyclins involved in the cell cycle
Transiently expressed at specific points in cell cycle
Lifespan of cyclins
Regulated at level of expression
Synthesised, then degraded
Conversion of cells from G0 to G1 by CDKs
1.c-Myc upregulates expression of cyclin D
Binds to inactive Cdk 4/6 complex
2. Different protein kinases add both inhibitory and activating phosphate to complex
3. Phosphatase removes the inhibitory phosphate, Cdk 4/6 Cyclin D complex becomes active, induced positive feedback loop by activating more phosphatases
Retinoblastoma Protein
A molecular ‘break’
prevents tumour formation
Rb may be implicated in cancer if inactive or missing
How Retinoblastoma Protein works
Rb inhibits E2F
CDK/cyclin complexes phosphorylate Rb - ‘sets E2F free’ - continuous process each CDK complex phosphorylates Rb
E2F = transcription factor and expresses genes necessary for DNA replication to continue
Which CDK/cyclin complex is involved in allowing S phase to happen
CDK2-cyclin E
Which CDK/cyclin complex is involved in allowing G2 phase to happen
CDK 2- Cyclin A
Which CDK/cyclin complex is involved in allowing M phase to happen
CDK 1 - cyclin B
Function of p53
Arrest cells with damaged DNA in G1
How does p53 work
- Activated by phosphorylation
- Bind to and activates transcription of p21
- Enzyme formed by expression of p21 inhibits Cyclin-CDK complexes
cell cannot continue
What amino acids can be phosphorylated by Cdks
Serine
Theronine
Tyrosine
Alanine (not phosphorylated by Cdks but can occur in other cellular processes mediated by kinases)
Sequence of differentiation of a benign tumour becoming malignant
Hyperproliferation > adenomatous polyps> severe dysplasia > adenocarcinoma > invasive cancer
How is activity of Cyclin-dependent kinases primarily regulated?
Cyclin binding and phosphorylation
- cylcins bind to Cdks to activate them
- phosphorylation of Cdks by CAKs further regulates activity through cell cycle
