1. Genetics NewsGenetics News Helen Fillmore talks today on therapies for neurodegenerative diseases. 12:30. Here. Problem Set 10 on line

2. On Our Plate Genetics of Cancer Clonal Nature of Cancer G6PD experiment Somatic vs. Germline Mutation RB: A Tumor Suppressor Gene Signal Transduction Oncogenes & Tumor Suppressors Progression of Cancer

3. Demonstration of Clonality What does the gel represent? (e.g. DNA fragments?) Protein with G6PD activity Protein from Leukocytes Protein from Skin cells What do “L” and “S” represent?

4. X B X B and X A X B Demonstration of Clonality SQ2 and 3: What is the mother’s genotype? Why two genotypes? Which was she born with? X A X B is the germline genotype

5. Demonstration of Clonality SQ4: Why three bands in skin cells? Lactate dehydrogenase??? 1 3 3 1 8 1 2 1 4 Glc-6-P dehydrogenase

6. Cancer: Infection or Clonal? What is meant by “A” and “B”? Why do some cells have “A” and others have “B”? Why do cells in panel C have a mixture of cell types? Why do cells in panel B have the same cell type? Fig. 2. Two models to explain cancer.... Half of the cells have an active X chromosome carrying the A allele and half have an active X chromosome carrying the B allele.

7. Control over Cell Division Mitosis Gap1 DNA synthesis Gap2

8. Control over Cell Division Build up of signal (cyclin-CDK complex) What happens if the cell is Rb - ? Hormones phosphate

9. The Menace of Familial Retinoblastoma Rb dominant Mutation rare (say 1 in 10 9 ) What is the result of a single Rb - mutation? What about here?

10. Study Question 9 Cell #1: Suddenly loses eye pigment enzyme Cell #2: Suddenly loses Rb Normal retinal cells don’t divide Derepressed cells divide once a day Cell #1Cell #2 Day 0Day 1Day 2Day 3Day 4 Ratio of Cell #1:Cell #2 after 30 days?

11. Study Question 8 Loss of RB in retinal cells causes retinoblastoma Sporadic cases show tumors only in one eye Inherited cases show tumors occur often in both eyes WHY?

12. Control over Cell Division Build up of signal (cyclin-CDK complex) Hormones

13. Signal Transduction: Environmental Signal

14. Signal Transduction: Activation of Receptor

15. Signal Transduction: Activation of Protein Kinase Ras

16. Signal Transduction: Activation of 2 nd Protein Kinase

17. Signal Transduction: Activation of 3 rd Protein Kinase

18. Signal Transduction: Activation of Transcription Factor E.g. Myc

19. Signal Transduction: Activation of Genes

20. Signal Transduction: Activation of Receptor No hormone Mutant signal transducing protein (e.g. Ras)

21. Signal Transduction: Activation of Genes No hormone Mutant signal transducing protein (e.g. Ras)

22. Control over Cell Division Build up of signal (cyclin-CDK complex) p53 Hormones Mismatch Repair Suicide? (Apoptosis)

23. Control over Cell Division Build up of signal (cyclin-CDK complex) Hormones

24. Oncogene vs Tumor Suppressor Oncogenes When mutated, stimulates cell division RAS - Stimulates protein kinase MYC - Transcriptional factor Tumor suppressors When mutated, releases division to cell block RB - Inhibits transcription factor P53 - Many functions (e.g. transcription factor)

25. Study Question 12 Protein monitors DNA for DNA damage If DNA damaged, protein blocks cell division Is protein tumor suppressor or from an oncogene?

26. Study Question 15 Lots of p53 mutations in dead people. WHY? A. p53 is prone to mutation? B. p53 is not prone to mutation, but leads to death? C. p53 related to feedback?

27. Study Question 15 A B C D

28. Causes of Particular Cancers Study Question 13 Why does the chromosome 8/14 translocation lead specifically to lymphomas? What is myc? What’s its threat? What is P imm ? Where is it on?