Control of Cell Proliferation

Question 1

what is cell proliferation?

Answer 1

the process that results in an increase of the number of cells
New daughter cells must be identical to parent cell in order maintain specialised function

Question 2

why must daughter cells need to be identical to parent cell?

Answer 2

New daughter cells must be identical to parent cell in order maintain specialised function

Question 3

what are the different phases of the cell cycle?

Answer 3

G1 phase, S phase, G2 phase, M phase

Question 4

what phases are part of interphase?

Answer 4

G1, S and G2 phases

Question 5

what happens in the G1 phase?

Answer 5

G1 phase (growth phase) - cell is signalled to replicate
- Cell produces proteins (from which organelles are synthesised)
- Replicates cell organelles
- Cell increases in size

Question 6

what happens in the S phase?

Answer 6

S phase – (synthesis)
- DNA replicates by semi-conservative replication

Question 7

what happens in the G2 phase?

Answer 7

G2 phase (growth phase)
- increase in cytoplasm and overall size of cell
- more organelle replication
- energy stores are increased

Question 8

what happens in the M phase?

Answer 8

M phase – mitosis phase; chromosome segregation & cytokinesis 🡪 forms two identical daughter cells

Question 9

what does the G1 checkpoint do and what is it regulated by?

Answer 9

G1 checkpoint (restriction point) – regulated by pRB (retinoblastoma protein)
ensures cell is large enough to divide and has enough nutrients to support daughter cells
If cell receives the go-ahead signal it continues with the cell cycle

Question 10

what happens in the G0 phase?

Answer 10

If cell does not receive a go-ahead signal in G1 (stop signal) the cell exits the cycle & switches to G0 (non-dividing state) (most somatic cells in G0)

Question 11

what happens in the G1/S checkpoint and what is it regulated by?

Answer 11

G1/S checkpoint – regulated by p53
checks DNA integrity (ensures that it isn’t damaged)
if damaged, cell cycle won’t continue, apoptosis occurs to ensure damaged DNA not passed onto daughter cells

Question 12

what happens in the G2 checkpoint?

Answer 12

ensures DNA replication in S phase has been successful
apoptosis occurs if stop signal is received

Question 13

what happens in the metaphase checkpoint?

Answer 13

ensures that all of the chromosomes are attached to spindle by their kinetochore
ensure equal amounts of chromatin are going to each daughter cell

Question 14

what is a kinetochore?

Answer 14

the protein complex at each centromere which serves as the attachment site for spindle microtubules.

Question 15

what happens to a cell after many replications?

Answer 15

Cells can either die, become a tumour or senescent
senescent = functioning cells outside of cell cycle

Question 16

what is the cell cycle regulated by?

Answer 16

Cyclin dependent Kinase - a protein which activates or deactivates another protein by phosphorylating them.

Question 17

how are Cdks activated?

Answer 17

They require cyclin to be activated
Cdks are activated by phosphorylation

Question 18

what increases the amount of cyclin?

Answer 18

Growth factors

Question 19

how do the different cyclins control the cell cycle?

Answer 19

The fluctuating levels of different cyclins at different times of the cell cycle activate different Cdks.
It is these Kinases give the go-ahead signals at the G1 and G2 checkpoints
By the G2 checkpoint enough cyclin has accumulated to form M-Cdk complexes which initiate mitosis
Later in mitosis, M-Cdk switches itself off by initiating a process which leads to the destruction of cyclin
Cdk, persists in the cell as an inactive form until it associates with new cyclin molecules synthesized during interphase of the next round of the cell cycle

Question 20

what are the different cyclins and Cdks that are required at different stages of cell cycle?

Answer 20

NB: Brackets contain the Cdk and the cyclin required to activate it:
Restriction point (G1 checkpoint) – (Cdk4 and cyclin D) and (Cdk2 and cyclin E/A) are required to give go ahead signals
G1/S phase – (Cdk2 and cyclin E/A) and (Cdk1 and cyclin A/B) are required to give go ahead signals
G2/M phase – (Cdk 1 and cyclin A/B) are required to give the go ahead signals

Question 21

what are inhibitory molecules?

Answer 21

INK (inhibits Cdk4) and CIP/KIP (inhibits broad spectrum Cdks)

Question 22

Explain the process that happens in the G1 checkpoint

Answer 22

In the absence of growth factors pRB binds to transcription factors of genes that are required for cell proliferation (transcription factor for cyclin gene)
Therefore, no cyclin is produced, CDK is not activated which prevents continuation of the cell cycle. (cell remains in G1)
In the presence of growth factors, GFs bind to receptors on the cell surface membrane which activate G1 Cdk and G1/S Cdk
G1 Cdk and G1/S Cdk then go on to phosphorylate pRB causing it to releases its binding on transcription factor regulators which then activates genes for cell proliferation (produce the cyclins)
pRB is a tumour suppressor protein: if there is a loss of function of pRB due to a mutation the cell cycle continues indefinitely, in the absence of growth factors, which results in tumour formation.

Question 23

Explain the process that happens in the G1/S phase checkpoint

Answer 23

DNA damage causes increase in protein p53 which activates transcription of p21 protein (an inhibitor of Cdk) preventing continuation of S phase
This gives time for DNA to repair
If there is only a small amount of DNA damage p53 can repair it
if damage too severe, p53 induces apoptosis
p53 is also a tumour suppressor protein 🡪 loss of function e.g. due to mutation 🡪 replication of damaged DNA 🡪 genome instability 🡪 increased rate of mutation.

Question 24

what are the consequences of checkpoint failure?

Answer 24

Proliferation of cells in absence of GFs
Increased genome instability = increased rate of mutation
Replication of damaged DNA
Segregation of incompletely replicated chromosomes
division of cells with wrong number of chromosomes

Question 25

what happens in the standard GF signalling pathway (GPCR)

Answer 25

GF binds to receptor- activates receptor via phosphorylation
Signal passed on to a Ras protein (type of G protein)
This causes a kinase cascade via phosphorylation
This continues into the nucleus where gene regulatory proteins are phosphorylated (activated)
Response 🡪 expression of genes required for cell proliferation

Question 26

define oncogenic

Answer 26

pertaining to the origin or development of tumours/cancer

Question 27

how can the signalling pathway become oncogenic?

Answer 27

A receptor may be mutated 🡪 constitutively active (no need for GF binding to be active)
This results in a deregulated cell proliferation🡪 cell becomes oncogenic 🡪 lead to tumour/cancer
(e.g. Her2 receptor involved in many breast cancer can cause deregulated cell proliferation 🡪 don’t need GFs to be activated)
A mutated constitutively active Ras protein can cause deregulated cell proliferation 🡪 lead to tumour/cancer
An over-expression of myc transcription factor (usually regulated by process above) can cause deregulated cell proliferation 🡪 cell becomes oncogenic 🡪 lead to tumour/cancer