A signal transducer and cancer Neurofibromin , ras , and cancer - utah

1. A signal transducer and cancer Neurofibromin, ras, and cancer - utah

2. Tumor suppressor genes Table 20.3 • Protein products suppress uncontrolled cell proliferation • Both copies must be inactivated for loss of function = 2 mutations in one cell required • Recessive • 2 hit model (Knudson 1971)

3. Example • Retinoblastoma • Eye cancer develops in childhood • Hereditary OR Sporadic – one eye only (13q14.1-q14.2.) 11 cases per million children aged 1 – 4 in US/yr treat with laser therapy

4. Sporadic – develop 2 mutations in 1 cell in 1 eye after birth Child born RB/RB in all cells  RB/rb in one cell

5. Hereditary – inherited 1 mutation in all body cells, need 1 more in any cell = Loss of heterozygosity (LOS) Child born RB/rb in all cells  rb/rb in one cell

6. Fig. 20.9

7. FYI The RB gene 180 kb  2.7 kb mRNA encodes pRB encodes 928 aa nuclear protein • 27 exons, largest is 200 bp • Many mutations found • Promoter, exons, splice sites • Point, frameshift, nonsense, missense

8. Function of normal pRBtumor suppressor protein pRB is a G1  S checkpoint protein Allows cell to progress to S phase

9. How does pRB work? EF2is a transcription factor that allows genes to be transcribed  S phase • pRB bindsEF2 EF2 cannot bind DNA Cell cycle arrested = cell does not move to S The big picture animation Plattsburgh

10. A Cyclin/CDKthenphosphorylates pRB

11. 3.EF2released to travel into nucleus Acts as a transcription factor  cell moves to S phase.

12. Cyclin then degraded (no more phosphorylation of pRB) EF2 bound to pRB If RB gene is mutant then 

14. Parent with high RB risk. Mutation changes amino acid his to tyr. GGTGATC vs GGTAATC Exon 18.

15. PCR

17. FYI: Examples of hereditary cancers (predisposition genes) • Breast-ovarian cancer syndrome 1 BRCA1 gene. 80 %lifetime chance of developing breast cancer and 60 percent lifetime chance of ovarian cancer. Tumor suppressor, chromosome 17 • Breast-ovarian cancer syndrome 2 BRCA2 gene. 80 % lifetime chance of developing breast cancer and a 20 percent lifetime chance for ovarian cancer. Tumor suppressor, chromosome 13 • Familial adenomatous polyposis hereditary colon cancer. APC gene. Individuals develop hundreds to thousands of polyps. Tumor suppressor, chromosome 5 • Familial melanoma increased chance of developing melanoma and may have an increased chance for pancreatic and brain tumors. A CKD inhibitor. • Hereditary nonpolyposis colon cancer (HNPCC) hereditary colon cancer resulting from an change in one of at least four genes. 80 % lifetime risk of colon cancer. Female family members have a 40 %to 60 % lifetime risk of developing uterine cancer. DNA repair • Von Hippel Lindau (VHL) syndrome VHL gene. increased risk of kidney cancer, tumors of adrenal gland, retina, and brain and spinal tumors. Tumor suppressor, chromosome 3. • Li Fraumeni - TP53 gene many cancers. Tumorsuppressor, chromosome 17.

18. Cancer: multi-step disease • Accumulation of mutations in a number of genes in single cell • Can build up over decades • Vogelstein model • FAP colorectal cancer

19. Colorectal cancer

20. FAP • APC tumor suppressor gene • mutation is inherited • (adenoma class I is benign tumor) • Mutation in Ras Oncogene • Mutation in Tumor suppressor gene DCC • (Adenoma class III) • mutation in Tumor suppressor gene TP53 • metastasis

21. p53 tumor suppressor • Involved in ~50% of cancers

22. Role of p53 tumor suppressor • Monitors signals that indicate DNA damage/mutation • Damage cell  increase p53 protein • Normal cell  p53 would inhibit cell growth but p53 has short half life

23. Damage DNA  p53  DNA repair, cell cycle arrest or apoptosis  genome integrity

24. When normal cells are damaged beyond repair, they are eliminated by apoptosis (A). Cancer cells avoid apoptosis and continue to multiply in an unregulated manner (B).

25. p53 can activate apoptosis pathway Apoptosis • Programmed cell death HeLa cell apoptosis OR Garland science

26. p53/p53 knockout mice • Develop normally, within 10 months 100% of mice have cancer

27. Example of TP53 gene hereditary cancer • Li-Fraumeni syndrome • Inherit one mutant copy of TP53 gene • One more mutation (single cell)….. • Develop a number of cancers • Bone, Blood cell, Brain, Breast, Colon, Bladder cancer • >90% lifetime risk of cancer • (Very rare, 17p13.1)

28. Evidence that p53 is a tumor suppressor • Moshe Oren • Weizmann Institute/Israel

29. angiogenesis • Tumor obtains its own blood supply • HHMI animation

30. metastasis • Tumor cells move to new location metastasis Pancreatic cancer  liver

31. Telomerase in cancer cells • Telomeres at ends of chromosomes • Chromosome shortens with each cell division • No telomerase in normal cells • Cancer cells make telomerase  immortalized

32. Types of cancer • Carcinomas; 90% of cancers • epithelial cells • Sarcomas; rare • tumors of connective tissues and muscle • Leukemias and lymphomas; 8%of tumors.  Basal cell carcinoma Kaposi’s sarcoma of blood vessels leukemia Hodkins lymphoma in lymph node