lecture outline, 11/30/05 34 cancerdstratto/bcor011_handouts/34_cancer.pdf•example: retinoblastoma...
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34 CancerLecture Outline, 11/30/05
• Review the Cell cycle• Cancer is a genetic disease• Oncogenes and proto-oncogenes
– Normally promote cell growth.– Become oncogenic after point mutations,
duplications, deletion of silencer, etc• Tumor Suppressor genes
– Normally inhibit cell growth.– Allow cell growth when damaged or deleted.
• Mutator genes• The multi-step model of cancer
Cancer is caused by mutantgenes
• Mutations in regulatory genes lead touncontrolled cell growth– Understanding gene regulation is one key
to understanding cancer• All cancers trace back to single cell
– Must accumulate multiple mutations, all inthe same cell lineage
Changes in growth properties ofcancer cells
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The incidence of human cancers increases markedly with ageIt takes a long time for the causative mutations to accumulate in a cell The Human Cell Cycle
~ 10 hours
~ 9 hours
~ 4 hours
~ 1 hour
Cell Cycle Regulators andCancer
Free E2F is atranscriptionactivator
Rb repressesE2F
Cyclin/Cdkinactivates Rb byphosphorylation
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P53 is a transcriptionfactor that activates p21,an inhibitor of cyclin/cdk2
Signaling pathways that regulatecell division
MUTATION
1 Growthfactor
2 Receptor
ppp p
pp
GTP
Ras
3 G proteinRas
GTP
HyperactiveRas protein(product ofoncogene)issues signalson its own
4 Protein kinases(phosphorylationcascade)
5 Transcriptionfactor (activator)
NUCLEUS
DNA
Gene expression
Protein thatstimulatesthe cell cycle
2 Protein kinases
UVlight
DNA damagein genome
1DNA
3 Activeformof p53
Defective ormissingtranscriptionfactor, such asp53, cannotactivatetranscription
MUTATION
Protein thatinhibitsthe cell cycle
EFFECTS OF MUTATIONS
Proteinoverexpressed
Cell cycleoverstimulated
Increased celldivision
Cell cycle notinhibited
Protein absent
(a) Cell cycle–stimulating pathway.This pathway is triggered by a growthfactor that binds to its receptor in theplasma membrane. The signal is relayed to a G protein called Ras. Like all G proteins, Rasis active when GTP is bound to it. Ras passesthe signal to a series of protein kinases.The last kinase activates a transcriptionactivator that turns on one or more genes for proteins that stimulate the cell cycle. If amutation makes Ras or any other pathway component abnormally active, excessive celldivision and cancer may result.
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(b) Cell cycle–inhibiting pathway. In this
2pathway, DNA damage is an intracellularsignal that is passed via protein kinasesand leads to activation of p53. Activatedp53 promotes transcription of the gene for aprotein that inhibits the cell cycle. Theresulting suppression of cell division ensuresthat the damaged DNA is not replicated.Mutations causing deficiencies in anypathway component can contribute to thedevelopment of cancer.
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(c) Effects of mutations. Increased cell division,possibly leading to cancer, can result if thecell cycle is overstimulated, as in (a), or notinhibited when it normally would be, as in (b).
Figure 19.12
Stimulation versus inhibition ofG1 progression
Stimulation of G1 progression
mitogens
rasmyc
pRB pRBPPPInhibition
S-phase entryS-phase entry
allowed
Inhibition of G1 progression
p27
PKB
anti-mitogen (TGF-β)
cyclin D / cdk4
pRB pRBPPPInhibition
S-phase entryS-phase entry
allowed
p15
DNA-damage
p21
p53
p16
?
cyclin D / cdk4
oncogenes tumor suppressor genes
Oncogenes• All are involved in positive control of cell growth
and division.– About 100 different oncogenes have been identified
• Can be various kinds of proteins:– Growth factors, regulatory genes involved in the
control of cell multiplication.– Protein kinases, add phosphate groups to target
proteins, important in signal transduction pathways.• “Proto-oncogenes”
– Normal form of the gene that is involved in positiveregulation of the cell cycle
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Genetic changes that can turnproto-oncogenes into oncogenes
Proto-oncogeneDNA
Translocation or transposition:gene moved to new locus,under new controls Gene amplification
Point mutationwithin a controlelement
Point mutationwithin the gene
OncogeneOncogene
Normal growth-stimulatingprotein in excess
Hyperactive ordegradation-resistant protein
Normal growth-stimulatingprotein in excess
Normal growth-stimulatingprotein in excess
Newpromoter
Figure 19.11
Translocation puts abl under the control of adifferent promoter
Translocation puts bcl near a new enhancerRas Proto-oncogene
• Mutated in 30% of all cancers.• A “molecular switch” in the signal
transduction pathway leading fromgrowth factors to gene expressioncontrolling cell proliferation:– GF → receptor → → Ras → → → TF →
target genes → growth.• A single amino acid change in Ras
protein can cause constant stimulationof the pathway, even in the absence ofgrowth factors.
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Receptor tyrosine kinases can activate rasras is a monomeric G-protein“molecular switch”
You’ve seen RASbefore . . .
Ras activation sets off a phosphorylation cascade
Mitogen ActivatedProteinKinasesMAPKs
Controls:-Transcription Factors-Translation Factors-Cell Division
MAPK
MAPKKK
MAPKK
10 100
1,000
100,000
PROBLEMS IN CANCER:PROBLEMS IN CANCER:
- Broken receptor – thinks ligand thereeven when it isn’t
- broken ras – won’t shut off
-broken MAPK – on all the time, even whennot phosphorylated
RESULT: continuous signal for cell to divideRESULT: continuous signal for cell to divide
Oncogenes act cooperatively intumor-induction
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Tumor Suppressor Genes• Normally inhibit cell growth• Example: retinoblastoma
– RB protein normally blocks a transcriptionfactor, E2F
p53 Gene
• Detects DNA damage• The “Last Gatekeeper”
– Involved in 50% of cancers– Often not malignant despite other cancer-causing
mutations until p53 is inactivated by mutation.• Two possible responses to DNA damage:
– 1) Acts as a Transcription Factor to activateexpression of p21, which inhibits CDK/G1 cyclinto halt the cell cycle; then activates DNA repair.
– 2) Triggers Apoptosis (programmed cell death) ifdamage can’t be repaied.
Apoptosis =controlled celldeath
Reduced cell death canalso lead to cancer
“executioner”proteins(caspases)break downthe cell
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http://www.cell-research.com/20014/20014cover.htm
Apoptosis pathways
Mutator genes• Cancer is caused by mutations, so factors
that increase mutation rate will increasecancer rate.– What kinds of genes would increase mutation
rate?– Example: BRCA1 and BRCA2
• Many environmental factors (carcinogens)also cause DNA damage or mutations, thatcan lead to cancer
Colon
1 Loss oftumor-suppressorgene APC (orother)
2 Activation ofRas oncogene
3 Loss oftumor-suppressorgene DCC
4 Loss oftumor-suppressorgene p53
5 Additionalmutations
Colon wall
Normal colonepithelial cells
Small benigngrowth (polyp)
Larger benigngrowth (adenoma)
Malignant tumor(carcinoma)
A multistep model for thedevelopment of colorectal cancer
Figure 19.13
(1) The clonal origin of tumors: each individualcancer is a clone that arises from a single cell.The progeny cells have growth advantage over thesurrounding normal cells.
(2) Cancer development is a multi-step process.Multiple mutations accumulated over periods ofmany years ----“multi-hit” model.