1. 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

3. Fig. 18-22 EFFECTS OF MUTATIONS Malignant tumor (carcinoma) Colon Colon wall Loss of tumor- suppressor gene APC (or other) Activation of ras oncogene Loss of tumor-suppressor gene DCC Loss of tumor-suppressor gene p53 Additional mutations Larger benign growth (adenoma) Small benign growth (polyp) Normal colon epithelial cells 5 4 2 3 1 The multiple-mutation model for the progression of cancer

5. Fig. 12-14 S G1G1 M checkpoint G2G2 M Control system G 1 checkpoint G 2 checkpoint

6. Rb (functional) Enhancer (distal control elements) Proximal control elements Poly-A signal sequence Termination region Downstream Promoter Upstream DNA Exon Intron

7. Rb (Loss of function) Enhancer (distal control elements) Proximal control elements Poly-A signal sequence Termination region Downstream Promoter Upstream DNA Exon Intron

8. Rb (Loss of function) Enhancer (distal control elements) Proximal control elements Poly-A signal sequence Termination region Downstream Promoter Upstream DNA Exon Intron 1.Substitution in ORF a. missense mutation makes non-functional protein AAG to GAG Lys replaced by Glu

9. Enhancer (distal control elements) Proximal control elements Poly-A signal sequence Termination region Downstream Promoter Upstream DNA Exon Intron 1.Substitution in ORF a. missense mutation makes non-functional protein b. nonsense mutation makes truncated (and non-functional) protein TGG to TGA Trp replaced by STOP Rb (Loss of function)

10. Enhancer (distal control elements) Proximal control elements Poly-A signal sequence Termination region Downstream Promoter Upstream DNA Exon Intron 1.Substitution in ORF a. missense mutation makes non-functional protein b. nonsense mutation makes truncated (and non-functional) protein 2.Insertion/ deletion in ORF (frameshift) makes truncated (and non-functional) protein Insert one A Frameshift during translation Rb (Loss of function)

11. Enhancer (distal control elements) Proximal control elements Poly-A signal sequence Termination region Downstream Promoter Upstream DNA Exon Intron 1.Substitution in ORF a. missense mutation makes non-functional protein b. nonsense mutation makes truncated (and non-functional) protein 2.Insertion/ deletion in ORF (frameshift) makes truncated (and non-functional) protein 3.Mutation in promoter or control element prevents transcription Mutation prevents RNA pol II binding Rb (Loss of function)

12. Enhancer (distal control elements) Proximal control elements Poly-A signal sequence Termination region Downstream Promoter Upstream DNA Exon Intron 1.Substitution in ORF a. missense mutation makes non-functional protein b. nonsense mutation makes truncated (and non-functional) protein 2.Insertion/ deletion in ORF (frameshift) makes truncated (and non-functional) protein 3.Mutation in promoter or control element prevents transcription 4.Mutation in intron alters splicing Mutation prevents splicosome binding Rb (Loss of function)

13. 1.Substitution in ORF a. missense mutation makes non-functional protein b. nonsense mutation makes truncated (and non-functional) protein 2.Insertion/ deletion in ORF (frameshift) makes truncated (and non-functional) protein 3.Mutation in promoter or control element prevents transcription 4.Mutation in intron alters splicing 5.Deletions of entire gene Rb (Loss of function)

14. Enhancer (distal control elements) Proximal control elements Poly-A signal sequence Termination region Downstream Promoter Upstream DNA Exon Intron Rb (Loss of function) 1.Substitution in ORF a. missense mutation makes non-functional protein b. nonsense mutation makes truncated (and non-functional) protein 2.Insertion/ deletion in ORF (frameshift) makes truncated (and non-functional) protein 3.Mutation in promoter or control element prevents transcription 4.Mutation in intron alters splicing 5.Deletions of entire gene 6. Gene becomes encased in hetrochromatin

17. Fig. 18-21a Receptor Growth factor G protein GTP Ras GTP Ras Protein kinases (phosphorylation cascade) Transcription factor (activator) DNA Hyperactive Ras protein (product of oncogene) issues signals on its own MUTATION NUCLEUS Gene expression Protein that stimulates the cell cycle (a) Cell cycle–stimulating pathway 1 1 3 4 5 2 Ras pathway: promotes cell growth

18. Fig. 18-21a Receptor Growth factor G protein GTP Ras GTP Ras Protein kinases (phosphorylation cascade) Transcription factor (activator) DNA Hyperactive Ras protein (product of oncogene) issues signals on its own MUTATION NUCLEUS Gene expression Protein that stimulates the cell cycle (a) Cell cycle–stimulating pathway 1 1 3 4 5 2

19. Ras (proto-oncogene) Enhancer (distal control elements) Proximal control elements Poly-A signal sequence Termination region Downstream Promoter Upstream DNA Exon Intron

20. Ras* (oncogene) Enhancer (distal control elements) Proximal control elements Poly-A signal sequence Termination region Downstream Promoter Upstream DNA Exon Intron

21. Ras* (oncogene) Enhancer (distal control elements) Proximal control elements Poly-A signal sequence Termination region Downstream Promoter Upstream DNA Exon 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)

22. Ras* (oncogene) Enhancer (distal control elements) Proximal control elements Poly-A signal sequence Termination region Downstream Promoter Upstream DNA Exon 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

23. Ras* (oncogene) Enhancer (distal control elements) Proximal control elements Poly-A signal sequence Termination region Downstream Promoter Upstream DNA Exon 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 binding 3.Mutation in exon prevent microRNA binding

24. Ras* (oncogene) Enhancer (distal control elements) Proximal control elements Poly-A signal sequence Termination region Downstream Promoter Upstream DNA Exon 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 binding 3.Mutation in exon prevent microRNA binding 4.Chromosomal rearrangement

25. Fig. 15-15 Deletion A B C D E F G HA B C E F G H (a) (b) (c) (d) Duplication Inversion Reciprocal translocation 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 RA B P Q R

26. Fig. 15-17 Normal chromosome 9 Normal chromosome 22 Reciprocal translocation Translocated chromosome 9 Translocated chromosome 22 (Philadelphia chromosome)

27. 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

28. Fig. 18-21b MUTATION Protein kinases DNA DNA damage in genome Defective or missing transcription factor, such as p53, cannot activate transcription Protein that inhibits the cell cycle Active form of p53 UV light (b) Cell cycle–inhibiting pathway 2 3 1 P53 pathway: inhibits cell growth

30. Fig. 18-21b MUTATION Protein kinases DNA DNA damage in genome Defective or missing transcription factor, such as p53, cannot activate transcription Protein that inhibits the cell cycle Active form of p53 UV light (b) Cell cycle–inhibiting pathway 2 3 1 P53 pathway: inhibits cell growth