Cell Replication

Question 1

What is the cell cycle?

Answer 1

Sequence of events where a cell duplicates its contents and divides in two

• duplication
• division
• co-ordination

Question 2

What causes cells to divide at different rates?

Answer 2

Embryonic vs adult cells

Complexity of system

Necessity for renewal

State of differentiation

Tumour cells?

Question 3

What are the stages of the cell cycle?

Answer 3

G0

G1

S

G2

Question 4

What is G0?

Answer 4

Quiescent phase —> cells go there in absence of stimulus

Cells not dormant —> non-dividing

Question 5

What cell cycle checkpoints are there?

Answer 5

G1 —> damaged DNA, unfavourable extracellular environment
- nutrients
- growth factors

S —> damaged or incompletely replicated DNA

G2 —> damaged or incompletely replicated DNA

M —> chromosome improperly attached to mitosis spindle

Question 6

How do cells leave G0?

Answer 6

Response to extracellular growth factors\

Growth factor binds to GF receptor on cell-surface
—> initiates intracellular signal pathway
—> increase in protein synthesis + decrease on protein degradation —> cell growth

MAP kinases involved

Question 7

What is c-Myc?

Answer 7

Transcription factor that promotes G0 to transition to G1 by stimulating the expression of cell cycle genes

Oncogene expressed in many tumours

Question 8

What are cyclin dependent kinases?

Answer 8

Entities part of key signalling events in the cell cycle
—>Phosphorylation + dephosphorylation at serine, threonine and tyrosine residues

Allow for tight control of the cell cycle

Present in all proliferating cells but only active when cyclin is bound

Question 9

Where do cyclins get their name from?

Answer 9

Their concentration within the cell fluctuate
—> production + degradation

Question 10

What events need to happen for a cell to move from G0 to G1?

Answer 10

Growth factor bonds to its receptor —> causes c-Myc expression
—> Induces expression of cyclin D —> binds to Cdk 4/6
—> moves cell into G1

Question 11

What is a protein kinase cascade?

Answer 11

Frequently the protein regulated by a kinase is another kinase

Leads to —> signal amplification
—> diversification
—> opportunity fo regulation

Question 12

What is the Cyclin-dependent kinases relevance to the cell cycle?

Answer 12

Present in all proliferating cells throughout the cycle

Activity regulated by:
—> interaction with cyclins
—> phosphorylation

Question 13

What is the cyclins relevance in the cell cycle?

Answer 13

Transiently expressed at specific points ion the cell cycle

Regulated at level of expression

Synthesised, then degraded

Question 14

Stages of Cdk activation

Answer 14

1. Inactive Cdk
2. Cyclin binds to Cdk —> cyclin:Cdk complex still inactive
3. Protein kinases phosphorylate Cdk at various sites
4. Activating protein phosphatase removes the inhibitory phosphate —> activates the complex

Question 15

How does positive feedback work in Cdk activation?

Answer 15

Once M-Cdk activated —> phosphorylatesCdc25 phosphatase
(now active) —> activates production of more M-Cdk

Helps drive cell from G2 to M phase rapidly

Question 16

How are cyclins turned off?

Answer 16

By ubiqutination

Ubiquitin molecules are stuck onto proteins that the cell wants to degrade by proteasome cell machinery

Question 17

How is direction and timing given to the cell cycle?

Answer 17

Cdk become sequentially active and stimulate synthesis of genes required for next phase

Cyclins susceptible to degradation —> hence cyclical activation

Question 18

What is retinoblastoma?

Answer 18

Protein that is a molecular break

Tumour suppressor
—> if missing or inactive —> issues with cell cycle progression

Abundant in all uncleared cells

Question 19

What does retinoblastoma do?

Answer 19

Active Rb sequesters a TF in an inactive form
—> TF cannot turn on genes needed for cell cycle progression
—> can’t bind to DNA and induce transcription (e.g DNA polymerase)

Question 20

What do mitogens do?

Answer 20

Activation of intracellular signalling through mitogens leads to production of G1-Cdk and G1/S-Cdk complexes
—> phosphorylate Rb inducing its inactivation
—> release TF
—> target genes such as DNA polymerase now
activated

Question 21

What is p53?

Answer 21

Arrests cells with damaged DNA in G1

Regularly being turned over which is why stabilisation is needed

Question 22

How does p53 work?

Answer 22

Recognises breaks in double stranded DNA

Induces the p21 gene which inhibit cyclin:Cdk complexes by binding them and sequestering them

Question 23

Oncogene: EGFR/HER2

Answer 23

Mutationally activated or over expressed in breast cancers

Herceptin antibody for the treatment of HER2+ metastatic breast cancers

Question 24

Oncogene: Ras

Answer 24

Mutationally activated in many cancers

Question 25

Oncogene: Cyclin D1

Answer 25

Overexpressed in 50% of breast cancers

Question 26

Oncogene: C-Myc

Answer 26

Overexpressed in many tumours

Question 27

What tumour suppressors are relèvent to the cell cycle?

Answer 27

Rb —> loss of function mutations in 80% of small cell lung cancer

p53 —> loss of function mutation in over 50% of all human cancers