Molecular Control Of The Cell Cycle Flashcards
Phase 1 of re entry to cell cycle
Initiation
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
G0
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 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
CDK’s
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
APC/C
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
Oncogenes
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