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Flashcards in Molecular Control Of The Cell Cycle Deck (17)


The non dividing phase of the cell cycle
Follow mitosis
->exit to differentiate
-> a cell where resources are limited-> sigmoid growth curve
Maintained by TGF-B
Stimuli-> withdrawal of growth factors or nutrients
In G0 can still return to cell cycle and proliferate-> can develop as cancer
Leave G0 when -> a cell that is fully differentiated and will never proliferate again-> muscle cells, neurones, final products of blood cell


Phase 1 of re entry to cell cycle

Immediate early entry genes:
Expression initiated by growth factors-> PDGF, FGF
-> c-jun, c-fos, c-myc produced
-> act as transcription factors-> activate delayed response genes
Constituently active mutant forms-> promote tumour formation as always active


Phase 2 of re entry to cell cycle

Re entry
Delayed response genes-> E2F and cyclin D
In quiescent cell-> Rb complexed with E2F-> inhibition of the transcription factors
Cyclin D binds CDK4 and 6-> become active protein kinases


Phase 4 of re entry in to cell cycle

Progression factors
Still E2F and cyclin D
Cyclin/CDK complex phosphorylates Rb-> cause Rb to release E2F
E2F activates transcription factors required to re enter the cell cycle


Cell cycle regulation

Cells in an active stage of proliferation are in the cell cycle
Progression is controlled by synthesis, degradation and the state of phosphorylation of cyclins
Cyclins activate various proteins by phosphorylation
Cyclin dependent kinase inhibitors modulate the activity of the cell cycle
Can only go forwards



Cyclin dependent kinases
Made constantly throughout the cell cycle
Require binding of a specific cyclin to be activated
Different cyclins are made at different times to control the cell cycle


Cell cycle check points

Surveillance systems in the cell nucleus that prevent cells replicating if they are damaged
Can either enter DNA repair or apoptosis if damaged


G1 to S phase transition

Monitors size and DNA integrity
Can only happen if E2F is free in the nucleus
During G1 E2F is normally bound to Rb
At G1 restriction point
-> phosphorylation of Rb via synthesis of cyclin D which complexes with CDK4 and 6 and then formation of cyclin E-CDK2
-> E2F released
If Rb is abnormal or cells over express cyclin D or CDK4-> cell check point will fail as Rb will tend to be phosphorylated


G2-M phase transition

DNA synthesis and damage monitoring
Regulated by the formation of CDK1-cyclin B
CDK1 is expressed throughout S and G2
Cyclin B expressed for transition in to M phase, destroyed shortly after
Is all DNA replicated?
Is environment favourable?
If so enter mitosis


Response to presence of cell damage

P53 is activated in the presence of cell damage-> causes increase in CDKIs-> p21 protein called WAF1
-> prevents phosphorylation of cyclins-> prevents phosphorylation of Rb so no free E2F-> can't enter S phase
If p53 is mutated-> danged cells can continue replicating-> propagates mutation
Levels of p53 rise in response to DNA damaging mutagens, insisting radiation or UV light
P53 also stimulates the production of GADD45 a gene repair enzymes
If DNA isn't repair p53 initiates apoptosis


Receptor tyrosine kinase pathway

1) growth factor binds to receptor
2) Ras is activated transiently exchanges GTP for GDPC
3) Ras sends signals to cascade of activated proteins
4) signal transduction proteins activate transcription factors
5) activation or repression of gene transcription


CDK phosphorylation and activation

In order for cyclins to bind to CDKs the CDKs need to be phosphorylated
CDK activating kinase phosphorylatesCDK to fully activate the complex
Wee 1 kinase -> inhibitory phosphorylation
Cdc25 phosphatase removes the inactivating phosphate


Inhibitors of CDK activity

CDK1-cyclin B-> p21 and CDK1
CDK4/6-cyclin D-> INK4, p16
CDK2-cyclin E-> p27
CIP/KIP non specific inhibitors


Ultimate regulation by proteolysis

Becomes activated by CDC20 binds APC/C
Active APC/C
-> ubiquitination of the CDK-cyclin complex-> arrests cell cycle
Binds to alpha catenin and degrades it
If APC/C is absent of mutated alpha catenin rises and drives cell proliferation



Proto oncogenes -> genes that code for the proteins involved in cell growth
Cellular oncogenes-> genes that code for the proteins in the development of neoplasia
Proto oncogenes can lead to tumour development by
-> mutation
-> gene amplification
-> abnormal gene promotors
means are no longer controlled-> oncogenic


Oncogene products

All key molecules in signal transduction and control of normal cell growth
TFs, c-fos, c-jun, c-myc are protoncogenes
C-fos and c-,myc alter cdk4/6 activity by regulating expression so cyclins and CKIs-> increase cyclin D expression and decease degradation, increase p27 degradation
Examples of products and functions
Ras-> GTP binding-> activated via a point mutation
Myc-> transcription activator-> translocation. Also n-myc


Tumour suppressor genes

Negative regulators of cell cycle
Either transcription factors of regulators of TFs
Inactivated in tumours
Rb is absent in tumours
P53 is also absent
APC is also absent

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