Understanding Genes and Cancer: Key Concepts and Mechanisms

1. Chapter 16 Genes and Cancer

2. Tomorrow’s quiz • Sordaria • Bioinformatics • PCR

3. Where we’re going • We’ll put cancer into perspective • Take a side trip into cell cycle regulation • Discuss TWO basic types of “cancer genes”- tumor suppressor and oncogenes • Learn about how to regulate the activity of proteins- phosphorylation and G-proteins.

4. Putting cancer into perspective • Mortality of the human race is stubbornly fixed at 100%- if you don’t die of cancer, something else WILL eventually kill you. • At least ¼ of us will get cancer, at least 1/5 will die from it- your book’s figures are worse (some of this depends upon how people treat skin cancer)

6. Characteristics of a cancer cell: • 1) uncontrolled growth; 2) ability to spread, or metastasize. W/o metastasis, a cancer is benign; when it’s able to spread, it becomes malignant. • NOTE: there are all sorts of other differences between cancerous and normal cells- this is just the basics.

7. all cancers are multi-gene effects- 3-7 mutations required for a cancer. Seen in the rarity of cancer in children, and the fact that, in spite of producing billions of cells daily, cancer remains rare.

8. Cell cycle perspective: • The cell goes through its cycle (16-5): At certain points there are checkpoints- places where the cell makes sure that things are OK before continuing. Things like a proper cell environment (signals from other cells, etc.), cell size, DNA being undamaged, etc. The THREE major checkpoints are G1/S and G2/M, and metaphase-anaphase

10. Cyclins • Cyclins- proteins whose concentrations rise and fall through the cell cycle. • KEY proteins!!!! • They work by activating CDK’s- protein kinases: proteins that phosphorylate other proteins, using ATP. This is a very, very common way of activating or inhibiting a proteins- • Different from allosteric interactions.

11. So the proteins to do these things are all sitting around, but inactive- waiting for their phosphate! The breakdown of cyclins is caused by their work- they start their own decline

13. So what’s this got to do with cancer?? • Checkpoints and signals for growth! • Tumor suppressor genes- keep damaged cells from replicating (brakes) • Proto-oncogenes- part of the mechanism to stimulate normal cell division. • Cancer is often due to defects in these genes.

14. Tumor Suppressor Genes: pRB and p53: • pRB: Defects produce an inherited form of cancer, retinoblastoma- cancer of the eye. If you inherit one bad copy, then the chances of another copy going bad in a cell are greatly increased (but not certain)

15. Other things have to contribute!!

16. Activates a BUNCH of genes needed for S phase!

17. p53: the “guardian of the genome”- • involved in 50-60% of all cancers. This gene product is made and degraded normally. However, when the DNA is damaged, two other “sentinels”, detect this damage; p53 is activated by PO4, stabilized, and acts as a TF that makes a product, p21, that prevents CDK’s from being active. • BRCA1 also is activated by P, stimulating DNA repair. • If the cell is too far gone, the activation of p53 results in apoptosis- the cell commits suicide

18. Net effect- cell cycle stops while damage is repaired. If not repairable- apoptosis! TF that produces p21, which binds to cyclin, stopping movement through the cell cycle

19. Oncogenes: • genes normally involved in cell division – proto-oncogenes- These genes are activated during cell division, usually by phosphorylation, and result in cell division being stimulated (Table 16-2). • Some are signal transducers; others are transcription factors • Discovered in cancer-causing retroviruses- caused cancer in mice, chickens, etc. Peyton Rous discovered RSV causing tumors in chickens in 1914

21. How do they go bad? • 1) point mutations: ras oncogene: a gene that transmits signals to divide from the surface to the nucleus. Ras is a G protein: a type of protein that it active when it has GTP bound to it, and inactive when it does not. Ras normally self-limits its action- when turned on by binding GTP, it soon turns itself off, b/c it has a GTpase activity built into the protein. The mutant forms- single nucleotide change- single AA change- results in a form that doesn’t turn itself off easily- hence a propensity for cancer.(21-8 in 5th ed.)

22. These are base substitutions that mean something!

23. With mutation, RAS stays on too long!

24. Overproduction • 2) either b/c a virus inserts near the gene, activating it; • or a translocation results in the gene being overactive. (21-12). The gene can also be overproduced by multiple copies of a gene being produced. • carried by a retrovirus; when the retrovirus inserts into a cell, it then has another copy of the oncogene, one that is very active; oncogenes were first discovered because they were part of retroviruses that caused cancer.

25. BCR= B cell receptor- immunoglobulin

27. Other considerations: carcinogens can increase the level of cancer- Ames test; some viruses are associated with cancer- the virally infected cells have altered genes that can result in cancer (Table 16.4)

30. Things to know • Cell cycle • Cyclin/CDK story- kinases and G proteins • Oncogenes and Tumor Suppressor • Rb and p53 stories • Oncogenes- Ras story- other means of overproduction. • A bit about viruses and cancer