Cell Replication 1

Question 1

What effects how fast a certain type of cell replicates?

Answer 1

Embryonic vs adult

Complexity of system

Necessity for renewal (intestinal epithelial vs hepatocyte)

Some never divide (neurons, cardiac myocytes)

Tumour cells

Question 2

What are the four phases of the cell cycle?

Answer 2

G1,S,G2,M

Gap 1 (G1)

S phase (DNA replication)

Gap 2 (G2)

M phase (mitosis)

G1,S and G2 make up interphase

Question 3

What is G0?

Answer 3

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

Question 4

How does a cell ‘decide’ whether or not it is favourable to cycle?

Answer 4

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

Question 5

What guards agains disastrous progression through the cycle?

Answer 5

Multiple checkpoints

One before each phase
As well as some others

Often reparing damaged or incomplete DNA

Question 6

How and why do cells leave G0?

Answer 6

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

Question 7

What is the role of c-Myc?

Answer 7

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

Question 8

What are cyclin dependant kinases?

Answer 8

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

Question 9

What are cyclins?

Answer 9

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

Question 10

What is an overview of the triggering to enter the cell cycle?

Answer 10

Growth factor

—>

Signals production of c-Myc

—>

Signals production of cyclin (D)

—>

Forms cyclin- CDK complex (D- CDK 4/6)

Question 11

What are protein kinase cascades?

Answer 11

Phosphorylation of one kinase molecule leads to the phosphorylation of another
And so on

Of the growth factors triggering tyrosine kinase

Question 12

What do protein kinase cascades do?

Answer 12

Leads to signa amplification

Diversification - allows different pathways to connect and trigger more pathways

Opportunity for regulation

Question 13

How are protein kinase cascades regulated?

Answer 13

Phosphorylation turns them on

De phosphorylation by phosphatases turn them off

Question 14

How does sequential phosphorylation and dephosphorylation activate CDKS

Answer 14

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

Question 15

What type of feedback is involved in CDKS?

Answer 15

Positive

Triggering one triggers a whole lot more

Leads to rapid entry into the M phase

Question 16

How are cyclins turned off?

Answer 16

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

Question 17

Why is the sequential activation of CDKS important?

Answer 17

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

Question 18

What is retinoblastoma?

Answer 18

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

Question 19

What do retinoblastomas do to resting cells?

Answer 19

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

Question 20

What do retinoblastomas do in proliferating cells?

Answer 20

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

Question 21

What is p53?

Answer 21

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

Question 22

What does activated p53 do?

Answer 22

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