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Tumor Supressor Gene

Mutations increasing risk of cancer. Tumor Supressor Gene. Non-functional TSG. “Loss of function” mutation. Proto- oncogene. Oncogene (Hyperactive or unregulated or overexpressed). “Gain of function” mutation. The multiple-mutation model for the progression of cancer. Colon. Fig. 18-22.

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Tumor Supressor Gene

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  1. Mutations increasing risk of cancer Tumor SupressorGene Non-functional TSG “Loss of function” mutation Proto-oncogene Oncogene (Hyperactive or unregulated or overexpressed) “Gain of function” mutation

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

  3. G1 checkpoint Fig. 12-14 Control system S G1 G2 M M checkpoint G2 checkpoint

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

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

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

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

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

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

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

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

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

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

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

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

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

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

  18. Ras* (oncogene) Mutation prevents repressor binding Poly-A signal sequence Enhancer (distal control elements) Proximal control elements Termination region Exon Intron Exon Intron Exon DNA Upstream Downstream Promoter • 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) • Mutation in control elements prevents repressor binding

  19. Ras* (oncogene) Loss of microRNA binding site Poly-A signal sequence Enhancer (distal control elements) Proximal control elements Termination region Exon Intron Exon Intron Exon DNA Upstream Downstream Promoter • 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) • Mutation in control elements prevents repressor binding • Mutation in exon prevent microRNA binding

  20. Ras* (oncogene) Translocation alters control element (or ORF) Poly-A signal sequence Enhancer (distal control elements) Proximal control elements Termination region Exon Intron Exon Intron Exon DNA Upstream Downstream Promoter • 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) • Mutation in control elements prevents repressor binding • Mutation in exon prevent microRNA binding • Chromosomal rearrangement

  21. A B C D E F G H A B C E F G H Deletion (a) A B C D E F G H A B C B C D E F G H Duplication (b) Fig. 15-15 A B C D E F G H A D C B E F G H Inversion (c) A B C D E F G H M N O C D E F G H (d) Reciprocal translocation M N O P Q R A B P Q R

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

  23. Mutations increasing risk of cancer Tumor Supressor Gene (e.g. P53) Non-functional TSG “Loss of function” mutation Usually recessive Proto-oncogene (e.g. Ras) Oncogene (Hyperactive or unregulated or overexpressed) “Gain of function” mutation Usually dominant

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

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

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