Lecture 5

Question 1

The Cell Cycle Control system is based on the
interaction between two families of proteins

Answer 1

Cyclins and
Cyclin Dependent Kinases (CDKs)

Question 2

CDKs are

Answer 2

serine/threonine kinases which depend on
associated regulatory subunits, the Cyclin proteins, to
function.

Question 3

The Cyclins associated with the CDKs activate

Answer 3

the
catalytic activity of their CDK partners.

Question 4

Active CDKs phosphorylate 100’s of target proteins to

Answer 4

trigger downstream events

Question 5

CDC2 AKA

Answer 5

CDK1

Question 6

Cell Cycle Mammals
CDK conc remains relatively constant throughout the cell
cycle BUT

Answer 6

Cyclin conc ‘cycles’ (levels go up and downhence its name!) (Cyclin B, D1, E AND A)

Cyclin D1 is present in phases of the cell cycle other than G1but following
G1/S transition
it is exported from the nucleus so it cannot influence cell cycle.
Degradation of cyclins is carried out by Ubiquitin Ligases

Question 7

Examples of Growth Factors which can be Broad
Specificity

Answer 7

Broad Specificity Growth Factors
* Epidermal Growth Factor (EGF)
* Platelet-Derived Growth Factor (PDGF)
* Insulin Like Growth Factor (IGF)
* Transforming Growth Factor-b (TGF-b)
* Fibroblast Growth Factor (FGF)

Question 8

GROWTH FACTORS are

Answer 8

Concentration Dependent
* Target Cell Dependent

Question 9

BUT THE ACTIVITY OF CYCLIN/CDKs CAN BE BLOCKED BY
THE ACTION OF

Answer 9

CYCLIN DEPENDENT KINASE INHIBITORS
(CDKIs)

Question 10

CDKIs CAN PROVIDE BRAKES ON CELL CYCLE
PROGRESSION-IMPORTANT DURING

Answer 10

DNA DAMAGE
RESPONSE AND ALSO DURING CELL GROWTH DECISION
MAKING STAGE (IE INPUT FROM GROWTH INHIBITORY
FACTORS SUCH AS TGFB LEADS TO INCREASED
EXPRESSION OF CDKIs p15 AND P21)

Question 11

CDK Inhibitors (CKIs)-Regulators of
the cyclin-CDKs.

Answer 11

INK4/CDKN2 family of proteins (p16, p15, p18 and p19)-originally
named as INK4 for inhibitors of CDK4. Also target CDK6-no effect on
CDK1 (aka CDC2) or CDK2. The INK4 proteins bind to CDK4/6 and
interfere with the binding of CDK4/6 to cyclin D.
* THE CIP/KIP/CDKN1 family members include p21cip1 and p27kip1
can inhibit all of the other cyclin-CDK complexes. These CKIs block
the ATP binding site.

Question 12

What ‘drives’ the cell to divideA simple overview of the G1 stage

Answer 12

Mitogenic signals (Growth factors) activate signalling
pathways which ultimately lead to the activation of
transcription factors (eg AP-1) which regulate the expression
of key cyclins such as CYCLIN D1.
* D-cyclins (D1, D2 and D3) once synthesised move to the
nucleus and associate with CDK4 and CDK6.
* CyclinD/CDK4 or CyclinD-CDK6 are phosphorylated by CAK
(CDK-activating kinase) in the activation loop of CDK4/6.
Activated CyclinD-CDK4/6 phosphorylates Rb.
* CyclinD-CDK4/6 also sequesters CKIs from CyclinE/CDK2 which
block cyclinE/CDK2 activity
* CyclinE/CDK2 further phosphorylates Rb,
‘hyperphosphorylation of Rb’ leads to E2F release which is a
key transcription factor for S phase gene expression

Question 13

Mitogenic Factors lead to the increased Expression of D-type
Cyclins

Answer 13

For full activity CAK (CDK activating kinase) phosphorylates the activation loops
of CDKs. Also inhibitory phosphorylations affecting CDK2 are removed by
a class of phosphatases called CDC25 (more in lecture on G2/M phase)
END RESULT-RB INACTIVATION AND E2F NOW ACTIVE FOR S-PHASE
GENE EXPRESSION

Mitogenic Factors lead to the increased Expression of D-type
Cyclins (D1/D2/D3) through up-regulated expression of specific
transcription factors which increase their expression

Question 14

Numerous signalling cascades converge on the Cyclin D1 promoter
Examples of Signalling Inputs controlling Cyclin D2 and D3 Expression…….

Answer 14

SOURCE OF SIGNAL: Various mitigens, interleukin receptor
SIGNALLING INTERMEDIATES; Myc, STAT3/5
CYCLIN: D2, D3