Transcript Cell Cycle - TeachLine

G1
• During G1 the cell must decide whether to arrest
and enter quiescence - G0 (or differentiate) or to
cycle and to proliferate.
• A normal cell does not make this decision on its
own but requires external signals in the form of
growth factors.
• Many transformed (cancer) cells do not require
growth factors in order to continue and proliferate.
• Many proteins involved in G1 regulation are
mutated or not correctly expressed in various
cancers.
The restriction point/Start
Start
The restriction point
Growth factors and receptors
………..
S-phase
Cyc D
cdk4
P
E2F
P
E2F
P
pRB
E2F
P
E2F
P
E2F E2F
E2F
E2F
Cyc E
cdk2
The Retinoblastoma (pRB)
and the p107, p130 pocket
proteins
Cyclin dependent kinase
inhibitors (CKI)
CKI
Cdk-cyclin
phase Involvement in cancer
p16ink4
cdk4/6 cyclin D
G1
Lost in many cancers
p21cip1/waf1 cdk2 cyclin A
S
Target of p53, required
for cell cycle arrest
p27kip1
G1
Required for cell cycle
arrest. Prognostic marker
cdk2 cyclin E/A
Cell cycle proteins and cancer
•
•
•
•
Cdk4 is over-expressed in many cancers
The p16 CKI (cyclin D/cdk4/6 is inactivated in many cancers.
ATM, Chk2 and p53 are mutated in many cancers.
High levels of the p27 CKI (cyclin E/cdk2 inhibitor) are a
positive prognostic marker in many cancers.
Skp1-Cdc53-F box
(+Rbx+cdc34(E2))
Checkpoints
For example:
For example:
For example:
A checkpoint protein
A checkpoint protein is required for cell
cycle arrest in response to damage until the
damage is repaired.
In other words
A checkpoint mutant will not arrest when
damaged and will continue to cycle into
catastrophe.
The ATM checkpoint mechanism
(ATM=Ataxia telangiectasia mutated)
(ATR=Ataxia telangiectasia related)
DNA damage checkpoints arrest
cells in G1
• The ATM protein senses double stranded DNA breaks.
• The ATR protein senses stalled replication forks and nucleotide
dimers
• The chk2 protein relays the stop signal by a fast and transient
and by a delayed and sustained response.
• The fast response degrades cdc25 that activates cdk2. Cdc25
degradation prevents cdk2 dephosphorylation and activation
and thereby prevents entry into S.
• The delayed response stabilizes the p53 transcription factor that
transcribes the p21 CKI (cyclin E/cdk2 inhibitor)
sensor
sensor
Signaling pathway
sensor
Signaling pathway
effect
Chk 2
ATM/R
P
Ub
Ub
PUbUb
P
p53
p53
Mdm2
Ub
Ub
Ub
Ub
Cyc E
p53
26S
Proteasome
p21
p21
p21
p21
p21
Cdk2
G1/S
Chk 2
Ub
Ub
Ub
Ub
P
CDC25
ATM/R
Ub
Ub
Ub
Ub
CDC25
Cyc E
P
Cdk2
26S
Proteasome
G1/S
18
19
23
24
Important points from G1 lesson
•
•
•
•
•
•
•
•
The restriction point.
Requirment of growth factors for cell proliferation.
Cancer cells do not require external factors for proliferation.
Cyclin D/cdk4/6 is synthesized in response to growth factors.
Cyclin D/cdk4/6 phosphorylates the pRB pocket protein.
pRB phosphorylation induces E2F transcription factor release.
E2F transcribe proteins essential for entry into S-phase.
Cyclin E/cdk2 is a key kinase for the entry into S-phase.