Transcript Cell Cycle and Cancer

Cell Cycle and Cancer
Daniel Hochhauser
MILESTONES IN CELL DIVISION:
TO CYCLE OR NOT TO CYCLE:
A CRITICAL DECISION IN CANCER
Malumbres and Barbacid
Nature Reviews Cancer 1, 222-231 (2001)
HALLMARKS OF CANCER
Hanahan and Weinberg
Cell 100,1 57-70 (2000)
Cell Cycle = round of chromosomal
replication in S phase followed by
segregation of the replicated
chromosomes into two daughter nuclei
during M phase
G2 / M phase transition is performed by a
protein kinase conserved throughout
eukaryotes
MPF - protein kinase catalytic subunit
p34 cdc2
- B-type cyclin
G2 / M phase transition is performed by a
protein kinase conserved throughout
eukaryotes
MPF - protein kinase catalytic subunit
p34 cdc2
- B-type cyclin
i.e a kinase and a cyclin
RESTRICTION POINT
Cells no longer require presence of serum to
commit themselves to initiating DNA
replication
RESTRICTION POINT
Cells no longer require presence of serum to
commit themselves to initiating DNA
replication
THE RESTRICTION POINT
IS ABROGATED IN CANCER
Uncontrolled cell proliferation
requires multi-step gene damage
eg
gain of function of oncogenes (accelerator)
and
loss of function of tumour suppressors (brakes)
CDKI
CYCLINS
ONCOGENES
when activated override brakes to cell
cycle progression
Cyclins and cyclin-dependent kinase
( cyclin D1, CDK4)
Tumour suppressor genes
when disabled allow accelerated cell
cycle progression
Cyclin-dependent kinase inhibitors
(p16, pRB)
CELL CYCLE
pRB
E2F
G1
NORMAL CELL CYCLE
P
pRB
E2F
pRB
G1/S
E2F
NORMAL CELL CYCLE
TS
P
pRB
E2F
pRB
E2F
NORMAL CELL CYCLE
G2/M
TS
E2F1,DHFR….
Viral Targeting of pRb
T Ag
HPVE7
E1A
pRB
INACTIVATION OF pRB in
TUMORS
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Retinoblastoma (two- hit)
small-cell lung cancer
soft tissue sarcoma
glioblastoma
breast cancer
bladder carcinoma
Inactivation of pRB by deletion, mutation,
phosphorylation results in increased ‘free’ E2F
Proliferation
E2F
Apoptosis
POSITIVE REGULATORS OF
G1 PHASE PROGRESSION
CDK-CYCLIN COMPLEXES
• Intrinsically inactive catalytic subunit
(CDK)
• Positive regulatory subunit (cyclin)
• Phosphorylation of conserved threonine
residue
CYCLIN D
• 3 Cyclin D genes
• synthesised by mid-G1 phase and maximum at
G1/S boundary
• stimulated by growth factors
• promote catalytic activity of CDK4 and CDK6
• Major substrate is retinoblastoma protein
• Cells lacking pRb do not require cyclin D1
activation
CYCLIN E
• synthesis at late G1 phase
• complexes with CDK2
NEGATIVE REGULATORS OF
G1 PHASE PROGRESSION
CYCLIN-DEPENDENT KINASE
INHIBITORS
CIP/KIP
INK4
p21cip1
p27kip1
p57kip2
p16INK4a
p15INK4b
p18INK4c
p19INK4d
INK4 CDKI
• specifically target CDK’s
• INK4 proteins sequester cdk4/6 into complexes
liberating cip/kip proteins
• ability to arrest in G1 dependent on intact pRb
• p16 and p19 alternative transcripts
• p16
– familial malignant melanoma
– ectopic expression results in G1 arrest
cell cycle
arrest
Cip/Kip CDKI
• p21= waf1=Sdi1 inhibits cyclin/CDK
function through cell cycle
Cip/Kip CDKI
• p21= waf1=Sdi1 inhibits cyclin/CDK function
through cell cycle
• universally inhibits cdks
Cip/Kip CDKI
• p21= waf1=Sdi1 inhibits cyclin/CDK function
through cell cycle
• universally inhibits cdks
• activated by p53 -critical in induction of cell cycle
arrest
CELL CYCLE GENE
ALTERATIONS IN CANCER
• pRb deletion / mutation
• p16 deletion / mutation
CELL CYCLE GENE
ALTERATIONS IN CANCER
• pRb deletion / mutation
• p16 deletion / mutation
• p27 inactivation (methylation)
CELL CYCLE GENE
ALTERATIONS IN CANCER
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pRb deletion / mutation
p16 deletion / mutation
p27 inactivation (methylation)
cyclin D1 overexpression
cyclin E overexpression
CDK4 overexpression
Keyomarsi et al N Engl J Med. 2002
p53
MDM2
CELL CYCLE PROGRESSION
SERINE-15
P
ATM
p53
CELL CYCLE ARREST
MDM2
Increasing endogenous CDK inhibition
Proteasome inhibitor PS-341 20S proteasome
Histone deacetylase inhibitors
Altering cyclin levels
Flavopiridol
Cyclin D
Rapamycin (CCI-779)
Cyclins D and A
Direct inhibitors of cyclin-dependent kinases
Flavopiridol
CDK1, 2, 4
UCN-01/staurosporine
CDK1, 2, 4, PKC, chk1
Cyclin D1overexpression, pRB deletion
Hanahan and Weinberg