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Molecular Genetics of Cancer
Oncogenes
Proto-oncogenes
Tumor Suppressor Genes
Oncogenes - when inappropriately activated or overexpressed, promote unregulated cell division.
Proto-oncogenes - normal cellular versions that can be
mutated to become oncogenes
Molecular Genetics of Cancer
Many proto-oncogenes are in signal transduction pathways
Growth factors
Growth factor receptors
Intracellular signaling proteins
Transcription factors
(Regulators of apoptosis)
(Cell cycle regulators)
Molecular Genetics of Cancer
Tumor Suppressor Genes
normally function to
- promote apoptosis
- inhibit cell proliferation
block the cell cycle
temporary – cell cycle arrest or exit
permanent – cell cycle exit (aka senescence)
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Molecular Genetics of Cancer - Tumor Suppressor Genes
p53 protein
- regulates progression through the cell cycle, especially at
the G1-S checkpoint.
- blocks entry into S phase if DNA is damaged, allowing time
for repair
- if repair fails, then p53 promotes apoptosis
Molecular Genetics of Cancer - Tumor Suppressor Genes
p53 protein
- transcription factor
-  turns on p21 - a cyclin-dependent kinase inhibitor
- p21 blocks activity of cyclinE-cdk2 (among others), the main
regulator of entry into S phase.
Figure 8.2(2) Cell Cycles of Somatic Cells and Early Blastomeres
Cyclin B
+ cdk1
MPF - G2-M
checkpoint
regulator
G1 - S and
G0 - G1 (cell cycle exit)
regulator Cyclin E
+ cdk2
G1-S checkpoint
regulator
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Figure 8.2(2) Cell Cycles of Somatic Cells and Early Blastomeres
Cyclin B
+ cdk1
Cdk
inhibitors
MPF - G2-M
checkpoint
regulator
p16
p21
Cyclin E
+ cdk2
G1-S checkpoint
regulator
p53 Functions & Targets Feedback
regulation
P53
Mdm2
Growth Arrest
p21
DNA Repair
Apoptosis
Bax
Apaf-1
PUMA
Fas
p53R2
Senescence –
permanent cell
cycle block
p53 Feedback Regulation
P53
Mdm2
P53 protein as TF turns on mdm2 gene
MDM2 protein ubitinates P53 protein
[ubiquitin targets proteins for degradation]
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Cell Cycle Regulation by pRB
CyclinD
pRB
cdk4
CyclinD/cdk4 inhibits Rb function
CyclinD
P
cdk4
pRB
pRB
P
P
P
pRB is phosphorylated to inhibit its function
- this promotes cell cycle progress (which unphosphorylated pRB blocks) RB – Retinoblastoma
Retinoblastoma – 1st human tumor suppressor gene discovered
Mutations in Rb gene cause eye tumors (esp. in children)
Molecular Genetics of Cancer - Tumor Suppressor Genes
pRB inhibits E2Fs, TFs that turn on genes needed for S phase, etc.
gray – proto-oncogenes
white – tumor suppressor genes
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Figure 6.24(1) The Wnt Signal Transduction Pathway
Both myc and
cyclinD are
target genes
p53 Regulation
- ARF checks proliferative signals (e.g., from Myc)
- P53 also regulates (indirectly) ARF & Myc
Myc
p14ARF P53
Mdm2
Molecular Genetics of Cancer - Tumor Suppressor Genes
An amazing genetic locus: INK4A
– 2 unrelated proteins from the same gene
p16INK4a
p14ARF
ARF: ‘alternate reading frame’
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