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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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4

3

5

(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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3

(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.