Cell Replication 1 Flashcards
What effects how fast a certain type of cell replicates?
Embryonic vs adult
Complexity of system
Necessity for renewal (intestinal epithelial vs hepatocyte)
Some never divide (neurons, cardiac myocytes)
Tumour cells
What are the four phases of the cell cycle?
G1,S,G2,M
Gap 1 (G1)
S phase (DNA replication)
Gap 2 (G2)
M phase (mitosis)
G1,S and G2 make up interphase
What is G0?
Quiescent phase
In the absence of stimuli cells go into G0
Most cells in the body which are differentiated to perform a specific function go into this (eg hepatocytes only replicate once a year)
Not dormant, just non dividing
Needs a stimulant to exit G0
First checkpoint
How does a cell ‘decide’ whether or not it is favourable to cycle?
Monitoring of external cycle
Nutrients?
Growth factors?
(Have to replicate all the DNA and double in size, does it have the means to do this?)
Or should it pause?
If DNA repair is needed
Or the cell is too far gone so it undergoes apoptosis
What guards agains disastrous progression through the cycle?
Multiple checkpoints
One before each phase
As well as some others
Often reparing damaged or incomplete DNA
How and why do cells leave G0?
Uses tyrosine kinase receptors
Indices a signalling cascade that it will be able to enter G1
Growth factors stimulate receptors (tyrosine kinase)
Signal amplification
Signal integration (Ras/Raf/MEK/ERK)
All of this increses protein synthesis and inhibits protein degradation, leading to cell growth
What is the role of c-Myc?
Transcription factor.
Stimulates production of cell cycle genes
Presence of a growth factor stimulates its expression
Promotes G0 to G1 transition
Oncogene- it is over expressed in many tumours
What are cyclin dependant kinases?
Csks
Kinases, so they phosphorylate molecules
Key to the cell progressing through the cycle
Phosphorylate molecules ( serine/threonine/tyrosine)
Allows excuisite control
Present in all proliferating cell (at constant
conc)
BUT only active when cyclin is bound
Also require phosphorylation for activation
What are cyclins?
Their concentrations within the cell fluctuate/cycle
Conc increased through to mitosis then drops at the beginning of interphase, repeat
Mitosis only occurs when there are cyclin-CDK complexes
What is an overview of the triggering to enter the cell cycle?
Growth factor
—>
Signals production of c-Myc
—>
Signals production of cyclin (D)
—>
Forms cyclin- CDK complex (D- CDK 4/6)
What are protein kinase cascades?
Phosphorylation of one kinase molecule leads to the phosphorylation of another
And so on
Of the growth factors triggering tyrosine kinase
What do protein kinase cascades do?
Leads to signa amplification
Diversification - allows different pathways to connect and trigger more pathways
Opportunity for regulation
How are protein kinase cascades regulated?
Phosphorylation turns them on
De phosphorylation by phosphatases turn them off
How does sequential phosphorylation and dephosphorylation activate CDKS
1- CDK is present in cell
2- cyclin binds (still inactive)
3- some protein kinases phosphorylate CDK
(Two sites, one activatory, other inhibitory)
4- activating protein phosphatase removes inhibitory phosphate. This activates the complex
What type of feedback is involved in CDKS?
Positive
Triggering one triggers a whole lot more
Leads to rapid entry into the M phase
How are cyclins turned off?
They have to as they cycle throughout the cell cycle
Ubiquitylation
This leads to the degradation of cyclin into amino acids
Leads to an inactive CDK
Why is the sequential activation of CDKS important?
As each one becomes active, it stimulates the next one along in the cycle to become active
Gives direction and timing
After each steps the old cyclin is degraded
What is retinoblastoma?
A molecular “break”
First identified through studies of a childhood eye tumour
Retinoblastoma protein (Rb) causes problems whemmmissing or inactive
It is a tumour surpressor abundant in all nucleated cells
What do retinoblastomas do to resting cells?
Active Rb sequesters inactive transcription factors and keeps them that way
(Especially the E2F family of TFs)
This means the TFs cannot turn on genes for cell progression
What do retinoblastomas do in proliferating cells?
The activation of intracellular signalling leads to production of G1-CDK and G1/S-CDK complexes
These phosphorylate Rb, inactivating it do it releases the transcription factor
Targets genes such as DNA polymerase and thymidine kinase can now be activated
What is p53?
A tumour suppressor gene
It arrests cells with damaged DNA in G1
P53 recognises double stranded breaks in DNA
The break leads to the activation of protein kinases that phosphorylate p53, stabilising and activating it
In absence of DNA damage, p53 is made and degraded
What does activated p53 do?
Binds to regulatory region of the p21 gene
This means p21 is expressed and translated into p21 mRNA
This transcribes p21 family members which act as CDK inhibitor proteins
Sequesters CDK-cyclin complexes in an inactive form so the S phase isn’t entered
