Tumor Supressor Gene

Tumor Supressor Gene Non-functional TSG

Mutations increasing risk of cancer

“Loss of function” mutation

Proto-oncogene Oncogene(Hyperactive or unregulated or overexpressed)

“Gain of function” mutation

Fig. 18-22

EFFECTS OF MUTATIONS

Malignant tumor(carcinoma)

Colon

Colon wall Loss of tumor-suppressor geneAPC (or other)

Activation ofras oncogene

Loss oftumor-suppressorgene DCC

Loss oftumor-suppressorgene p53

Additionalmutations

Larger benigngrowth (adenoma)

Small benigngrowth (polyp)

Normal colonepithelial cells

5

42

3

1

The multiple-mutation model for the progression of cancer

Fig. 12-14

SG1

M checkpoint

G2M

Controlsystem

G1 checkpoint

G2 checkpoint

Rb (functional)

Enhancer(distal control elements)

Proximalcontrol elements

Poly-A signalsequence

Terminationregion

DownstreamPromoterUpstream

DNAExonExon ExonIntron Intron

Rb (Loss of function)




Terminationregion







Terminationregion



1. Substitution in ORFa. missense mutation makes non-functional protein

AAG to GAGLys replaced by Glu




Terminationregion



1. Substitution in ORFa. missense mutation makes non-functional proteinb. nonsense mutation makes truncated (and non-functional) protein

TGG to TGATrp replaced by STOP





Terminationregion




2. Insertion/ deletion in ORF (frameshift) makes truncated (and non-functional) protein

Insert one AFrameshift during translation





Terminationregion




2. Insertion/ deletion in ORF (frameshift) makes truncated (and non-functional) protein3. Mutation in promoter or control element prevents transcription

Mutation prevents RNA pol II binding





Terminationregion




2. Insertion/ deletion in ORF (frameshift) makes truncated (and non-functional) protein3. Mutation in promoter or control element prevents transcription4. Mutation in intron alters splicing

Mutation prevents splicosome binding



2. Insertion/ deletion in ORF (frameshift) makes truncated (and non-functional) protein3. Mutation in promoter or control element prevents transcription4. Mutation in intron alters splicing5. Deletions of entire gene





Terminationregion





2. Insertion/ deletion in ORF (frameshift) makes truncated (and non-functional) protein3. Mutation in promoter or control element prevents transcription4. Mutation in intron alters splicing5. Deletions of entire gene6. Gene becomes encased in hetrochromatin

Fig. 18-21a

Receptor

Growthfactor

G protein GTP

Ras

GTP

Ras

Protein kinases(phosphorylationcascade)

Transcriptionfactor (activator)

DNA

HyperactiveRas protein(product ofoncogene)issuessignalson its own

MUTATION

NUCLEUS

Gene expression

Protein thatstimulatesthe cell cycle

(a) Cell cycle–stimulating pathway

11

3

4

5

2

Ras pathway: promotes cell growth

Fig. 18-21a

Receptor

Growthfactor

G protein GTP

Ras

GTP

Ras

Protein kinases(phosphorylationcascade)

Transcriptionfactor (activator)

DNA

HyperactiveRas protein(product ofoncogene)issuessignalson its own

MUTATION

NUCLEUS

Gene expression

Protein thatstimulatesthe cell cycle

(a) Cell cycle–stimulating pathway

11

3

4

5

2

Ras (proto-oncogene)




Terminationregion



Ras* (oncogene)




Terminationregion



Ras* (oncogene)




Terminationregion



Base substitution

1. Missense mutation in ORF results in altered protein with altered properties(e.g. no longer binds a negative regulator, or no longer requires a positive regulator)

Ras* (oncogene)




Terminationregion



Mutation prevents repressor binding


2. Mutation in control elements prevents repressor binding

Ras* (oncogene)




Terminationregion



Loss of microRNA binding site


2. Mutation in control elements prevents repressor binding3. Mutation in exon prevent microRNA binding

Ras* (oncogene)




Terminationregion



Translocation alters control element (or ORF)


2. Mutation in control elements prevents repressor binding3. Mutation in exon prevent microRNA binding4. Chromosomal rearrangement

Fig. 15-15

DeletionA B C D E F G H A B C E F G H(a)

(b)

(c)

(d)

Duplication

Inversion

Reciprocaltranslocation

A B C D E F G H

A B C D E F G H

A B C D E F G H

A B C B C D E F G H

A D C B E F G H

M N O C D E F G H

M N O P Q R A B P Q R

Fig. 15-17

Normal chromosome 9

Normal chromosome 22

Reciprocaltranslocation Translocated chromosome 9

Translocated chromosome 22(Philadelphia chromosome)

Tumor Supressor Gene(e.g. P53)

Non-functional TSG

Mutations increasing risk of cancer

“Loss of function” mutation

Proto-oncogene(e.g. Ras)

Oncogene(Hyperactive or unregulated or overexpressed)

“Gain of function” mutation

Usually recessive

Usually dominant

Fig. 18-21b

MUTATIONProtein kinases

DNA

DNA damagein genome

Defective ormissingtranscriptionfactor, suchas p53, cannotactivatetranscription

Protein thatinhibitsthe cell cycle

Activeformof p53

UVlight

(b) Cell cycle–inhibiting pathway

2

3

1

P53 pathway: inhibits cell growth

Fig. 18-21b

MUTATIONProtein kinases

DNA

DNA damagein genome

Defective ormissingtranscriptionfactor, suchas p53, cannotactivatetranscription

Protein thatinhibitsthe cell cycle

Activeformof p53

UVlight

(b) Cell cycle–inhibiting pathway

2

3

1

P53 pathway: inhibits cell growth

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Tumor Supressor Gene