Cell replication Flashcards
When are cells in G0 (quiescent phase)?
In absence of stimulus, cells go into G0
or
differentiated cells (neurones, hepatocytes)
What causes cells to leave G0?
In response to growth factors ( extracellular factors )
Signal amplification
Signal integration/modulation from other pathways
Ras/Raf/MEK/ERK
Examples of signalling proteins? (If these are mutated cancer risk increases)
Ras/Raf/MEK/ERK
How does a cell transition from G0 to G1?
growth factor stimulate c-Myc - a transcription factor
acts as a oncogene
c- Myc : growth factor signalling pathways induces expression of c-Myc. stimulates expression of cell cycle
What are Cyclin-dependent Kinases?
They are found inactive in proliferative cells.
Become activated when a cyclin binds
They phosphorylate molecules to activate or inactivate a protein
molecule examples : serine / threonine / tyrosine
Why can Serine, Threonine and Tyrosine be phosphorylated?
Due to their hydroxyl groups
What causes production and degradation, the levels of cyclins or the levels of CDKs?
Levels of cyclin as they fluctuate.
CDKs are always present in same concentration
Only the cyclin : Cdk complex is active during mitosis
What CDK does cell cycle entry require?
C-Myc promotes CDK4/6 - Cyclin D complex
Allows progression to S phase
Why are protein Kinase Cascades useful?
Kinases can be regulated by other kinases and this can cause both signal amplification/diversification of pathways or an opportunity for regulation
What causes a CDK-Cyclin complex to go from inactive to active?
The CDK has inhibitory phosphates and activating phosphates both bound to it
An activating protein phosphatase needs to remove the inhibitory phosphate
a cyclin will join a CDK but the complex is inactive
an activating protein phosphatase will remove the inhibitory phosphate on the CDK
activate + positive feedback
How are Cyclins removed from the CDK-Cyclin complex?
Ubiquitylation of cyclin ( signal on Cyclin that represents destroy me)
leaving a inactive CDK
How do CDKs-Clyclins regulate expression of the next complex?
an example?
Once active they stimulate synthesis of genes required for next phase.
e.g. ( G1 ) Cdk4/6-cyclin D leads to ( S ) Cdk2-cyclin E leads to (G ) Cdk2-cylin A leads to ( mitosis ) Cdk1-cyclin B
How is cell growth carried out?
Intracellular signalling pathways which drive proteins synthesis increase levels of proteins and since protein degradation is inhibited there is a net increase in protein.
How does Retinoblastoma protein act as a brake on cell proliferation?
isolates transcription factor in an inactive form so cannot turn on genes needed for cell cycle progression
Tumors seen in eyes in childhood if the Rb protein is MISSING as there is a lack of a tumour supprssor
How does the Rb brake become released?
Phosphorylation of Rb by G1-Cdk / G1/S-Cdk complexes
Inactivates Rb releasing transcription factor, allowing translation and cell proliferation
What is E2F and why is it important?
It is a transcription factor
Allows cell cycle progression once Rb is inactivated. Allows Cyclin E to bind to Cdk2 for S phase to begin
What if there are cells with damaged DNA in G1?
What does inactive p53 do?
p53 recognises the break in the DNA and protein kinases are activated.
These phosphorylate p53 activating it.
What does active p53 do?
In presence of DNA damage it binds to regulatory region of p21 gene. transcribing p21 mRNA = p21 protein
What does the p21 family do?
Inhibits Cyclin-Cdk complexes by binding to it
What examples of overexpression can cause cancer?
Regulatory proteins e.g. Ras Cyclin D1 C-Myc EGFR/HER2
What examples of loss of expression can cause cancer?
Regulatory proteins such as suppressors
Rb ( lung cancers )
p53 ( all human cancers, need mutation of both copies of the gene)
Extra missed info?
Cell cycle : duplication , division, co-ordination
- interphase : G1 + S + G2
- Cell cycle checkpoints (5) : external environment must have nutrients and growth factors,
G1 checkpoint : is enironment favourable = enter S phase
G2 checkpoint : is dna replicated, is dna damage repaired = enter mitosis
Mitosis checkpoint : are chromosomes properly attached to mitotic spindle = pull apart chromosomes
If repair cannot work undergo apoptosis
Growth factor ( mitogen signalling ) - for cell doubling in size