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
Rb (functional)
Enhancer(distal control elements)
Proximalcontrol elements
Poly-A signalsequence
Terminationregion
DownstreamPromoterUpstream
DNAExonExon ExonIntron Intron
Rb (Loss of function)
Enhancer(distal control elements)
Proximalcontrol elements
Poly-A signalsequence
Terminationregion
DownstreamPromoterUpstream
DNAExonExon ExonIntron Intron
Rb (Loss of function)
Enhancer(distal control elements)
Proximalcontrol elements
Poly-A signalsequence
Terminationregion
DownstreamPromoterUpstream
DNAExonExon ExonIntron Intron
1. Substitution in ORFa. missense mutation makes non-functional protein
AAG to GAGLys replaced by Glu
Enhancer(distal control elements)
Proximalcontrol elements
Poly-A signalsequence
Terminationregion
DownstreamPromoterUpstream
DNAExonExon ExonIntron Intron
1. Substitution in ORFa. missense mutation makes non-functional proteinb. nonsense mutation makes truncated (and non-functional) protein
TGG to TGATrp replaced by STOP
Rb (Loss of function)
Enhancer(distal control elements)
Proximalcontrol elements
Poly-A signalsequence
Terminationregion
DownstreamPromoterUpstream
DNAExonExon ExonIntron Intron
1. Substitution in ORFa. missense mutation makes non-functional proteinb. nonsense mutation makes truncated (and non-functional) protein
2. Insertion/ deletion in ORF (frameshift) makes truncated (and non-functional) protein
Insert one AFrameshift during translation
Rb (Loss of function)
Enhancer(distal control elements)
Proximalcontrol elements
Poly-A signalsequence
Terminationregion
DownstreamPromoterUpstream
DNAExonExon ExonIntron Intron
1. Substitution in ORFa. missense mutation makes non-functional proteinb. nonsense mutation makes truncated (and non-functional) protein
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
Rb (Loss of function)
Enhancer(distal control elements)
Proximalcontrol elements
Poly-A signalsequence
Terminationregion
DownstreamPromoterUpstream
DNAExonExon ExonIntron Intron
1. Substitution in ORFa. missense mutation makes non-functional proteinb. nonsense mutation makes truncated (and non-functional) protein
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
Rb (Loss of function)
1. Substitution in ORFa. missense mutation makes non-functional proteinb. nonsense mutation makes truncated (and non-functional) protein
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
Rb (Loss of function)
Enhancer(distal control elements)
Proximalcontrol elements
Poly-A signalsequence
Terminationregion
DownstreamPromoterUpstream
DNAExonExon ExonIntron Intron
Rb (Loss of function)
1. Substitution in ORFa. missense mutation makes non-functional proteinb. nonsense mutation makes truncated (and non-functional) protein
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)
Enhancer(distal control elements)
Proximalcontrol elements
Poly-A signalsequence
Terminationregion
DownstreamPromoterUpstream
DNAExonExon ExonIntron Intron
Ras* (oncogene)
Enhancer(distal control elements)
Proximalcontrol elements
Poly-A signalsequence
Terminationregion
DownstreamPromoterUpstream
DNAExonExon ExonIntron Intron
Ras* (oncogene)
Enhancer(distal control elements)
Proximalcontrol elements
Poly-A signalsequence
Terminationregion
DownstreamPromoterUpstream
DNAExonExon ExonIntron Intron
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)
Enhancer(distal control elements)
Proximalcontrol elements
Poly-A signalsequence
Terminationregion
DownstreamPromoterUpstream
DNAExonExon ExonIntron Intron
Mutation prevents repressor binding
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)
2. Mutation in control elements prevents repressor binding
Ras* (oncogene)
Enhancer(distal control elements)
Proximalcontrol elements
Poly-A signalsequence
Terminationregion
DownstreamPromoterUpstream
DNAExonExon ExonIntron Intron
Loss of microRNA binding site
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)
2. Mutation in control elements prevents repressor binding3. Mutation in exon prevent microRNA binding
Ras* (oncogene)
Enhancer(distal control elements)
Proximalcontrol elements
Poly-A signalsequence
Terminationregion
DownstreamPromoterUpstream
DNAExonExon ExonIntron Intron
Translocation alters control element (or ORF)
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)
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