Cell replication Flashcards
What(super-generally) is the cell cycle?
Orderly sequence of events in which a cell duplicates its contents and divides in two.
Duplication
Division
Co-ordination
What factors control cells’ rates of division?
Embryonicity/Adolescence
Complexity of system
Necessity for renewal
State of differentiation
What phases make up the cell cycle?
What is G0 and what causes it?
G0 – quiescent phase
In the absence of stimulus, cells go into G0
Most cells in the body which are differentiated to perform specific functions
Cells are not dormant, but are non-dividing
e.g. neurons
skeletal muscle
hepatocytes
What is checked at the G1 checkpoint?
Environment favourability
What is checked at the G2 checkpoint?
Is DNA replicated?
Is all DNA damage repaired?
What is checked at the mitosis checkpoint?
Are all chromosomes attached to the mitotic spindle?
What does c-Myc do and what kind of gene is it?
c-Myc promotes G0 to G1 transition
c-Myc is an oncogene(Transcription factor) - overexpressed in many tumours
How do growth factors stimulate cell growth e.g Ras/Raf/MEK/ERK
Progression from G0 to G1 through intracellular signalling pathways
Signal amplification
Signal integration/ modulation by other pathways
When are Cdks active in cells?
When a cyclin is bound
How does cyclin concentration and Cdk activity change over the cell cycle?
What cyclin/Cdk complex is required for cell cycle entry?
Cdk 4/6:cyclin D complex
What does the protein kinase cascade function lead to?
Signal amplification
Diversification
Opportunity for regulation
What Cdks are present in cells, when are Cdks present in the cell and what regulates their activity?
Cdk1, Cdk2, Cdk4, Cdk6
Present in proliferating cells throughout cell cycle
Interaction with cyclins
Phosphorylation
What cyclins are present in cells, when are cyclins present in the cell and what regulates their activity?
CyclinA, CyclinB, CyclinD, CyclinE
Transiently expressed at specific points in the cell cycle
Regulated at level of expression
Synthesised, then degraded
Outline how sequential phosphorylation and dephosphorylation leads to Cdk activation
- Cyclin is added to Cdk
- Protein kinases add inhibitory and excitatory phosphates
- Activating protein phosphatase removes inhibitory phosphate
- Cdk is active
How does positive feedback propagate Cdk function?(2)
- By stimulating inactivating phosphatases
- By inhibiting inhibitory kinases
How do M and S cyclin levels vary around the cell cycle?
S cyclin production starts in G1, activates S-Cdk in S phase
M cyclin production starts in G2, activates M-Cdk in M phase
How are Cdks ‘turned off’
Ubiquitination
Ubiquitin protein binds to cyclin, inactivating Cdk
What is retinoblastoma?
A tumour suppressor gene abundant in nucleated cells
What causes the cell cycle to be unidirectional?
Cdks become sequentially active and stimulate synthesis of genes required for next phase, e.g. cyclin D/Cdk4/6 stimulates expression of cyclin E – gives direction and timing to cycle
How does mitogen signalling work?
Intracellular signalling cascade leading to increases protein synthesis as well as decreased protein degradation
How does retinoblastoma(Rb) decrease cell proliferation?
Active Rb sequesters a transcription factor (TF) in an inactive form
The TFs cannot turn on genes needed for cell cycle progression
e.g. DNA polymerase
Thymidine kinase
How is retinoblastoma inactivated?
Activation of intracellular signaling leads to production of G1-Cdk and G1/S–Cdk complexes
They can phosphorylate Rb inducing the inactivation of Rb and release of the TF.
Target genes such as DNA polymerase and thymidine kinase can now activated.
What do E2F family members accomplish?
E2F family members regulate the expression of several genes need for cell cycle progression
How does p53 arrest cells with damaged cells in G1?
Give 4 oncogenes and how they affect the cell cycle?
EGFR/HER2 mutationally activated or over expressed in breast cancers Herceptin antibody for the treatment of HER2+ metastatic breast cancer
Ras mutationally activated in many cancers
Cyclin D1 overexpressed in 50% of breast cancers
C-Myc overexpressed in many tumours
Give 2 tumour suppressor genes and how they affect the cell cycle?
Rb loss of function mutations in 80% of small cell lung cancers
p53 loss of function mutations inover 50% of all human cancers
