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http://www.youtube.com/watch?v=Q6ucKWIIFmg&feature=related

http://www.youtube.com/watch?v=Q6ucKWIIFmg&feature=related. Cell Cycle, Cancer, & Chemotherapy. Learning Objectives: Explain the difference between normal and cancer cells. Describe the stages of the cell cycle and what occurs during each stage.

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http://www.youtube.com/watch?v=Q6ucKWIIFmg&feature=related

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  1. http://www.youtube.com/watch?v=Q6ucKWIIFmg&feature=related

  2. Cell Cycle, Cancer, & Chemotherapy Learning Objectives: • Explain the difference between normal and cancer cells. • Describe the stages of the cell cycle and what occurs during each stage. • List the three major places in the cell cycle where chemotherapy agents work. • Explain where the cell cycle has checkpoints and what these checkpoints are testing for. • Predict the effects of losing one of the checkpoints. • Understand what a tumor suppressor gene is and what an oncogene is and how they relate to checkpoint proteins. • Explain ways the cell cycle can be mis-regulated and how this leads to cancer.

  3. Why Do We Care About Cancer? • 2nd Leading cause of death in the US, behind heart disease • Around 500,000 Americans are expected to die this year from cancer • In 2010 GA will have an estimated 40,500 new cases of cancer • The total economic impact of cancer in the US is estimated to be 228 billion dollars • Taken from American Cancer Society and NIH

  4. Cancer: Unregulated Cell Division

  5. Cell Division: One part of the cell cycle Cell Cycle: How cells normally reproduce to replace cells Cancer • Mis-regulating the cell cycle. • Cells divide when they aren’t supposed to. • Cells divide in a place they aren’t supposed to. • Need to understand how the cell is coordinating this process • Understanding can lead to cancer treatments (chemotherapy)

  6. Clicker Question 1 Fighting Cancer • Death rates are lower since 1980 for all of the following female cancers, EXCEPT: • Breast • Lung • Colorectal • Uterus

  7. Chemotherapy Treatments Work at various stages to stop an overactive cell cycle • Inhibitors of Cell Growth (Growth Factor Proteins e.g. hormones) • Inhibitors of DNA Duplication • Inhibitors of Cell Division Where, when, and how do they work?

  8. Group Assignment: Part 1 Cell Cycle Overview On your sheet of paper, use these terms below to mark the arrows and place the pictures of the cell at different stages to create your own cell cycle diagram. Chromosome Duplication Chromosome Separation Cell Growth 2 Cell Division Cell Growth 1

  9. Group Assignment: Part 2 Chemotherapy Agents Indicate on your diagram where the three major types of chemotherapy agents would work: Inhibitors of DNA Duplication Inhibitors of Cell Division Inhibitors of Cell Growth

  10. Clicker Question 2 What would happen if the cell cycle proceeded normally, except that cell division did not occur? • The cell growth phases would become shorter. • The separation of chromosomes couldn’t occur. • The resulting cells would get smaller and smaller. • Cells without nuclei would be formed. • A large cell with multiple nuclei would result.

  11. Group Assignment: Part 3 There are three major points where the cell checks the progress of the cell cycle to insure that all is ready to proceed to the next step. Place these three “Checkpoints” on your diagram: Checkpoints 1 2 1. Cell Size Big Enough? DNA undamaged before copying? 2. All Chromosomes Attached to spindle and aligned? 3 3. All Genetic Material Duplicated? Environment Favorable?

  12. III I Clicker Question 3 Indicate the location of each cell cycle checkpoint Cell Size Big Enough? DNA undamaged before copying? All Chromosomes attached to spindle and aligned? All Genetic Material Duplicated and undamaged? Environment Favorable? IV • II, 3; III, 2; IV, 1 • II, 1; III, 2; IV, 3 • I, 1; II, 3; IV, 2 • II, 1; III, 3, IV, 2 II

  13. Clicker Question 4 DNA damage such as double strand breaks are detected at G1/S checkpoint by a master kinase called ATM. ATM kinase activates another kinase called p53 that halts the cell cycle at that checkpoint. If you were testing a new drug designed to activate the p53 protein, you could look for cells that were successfully arrested at this G1/S checkpoint by: • comparing DNA levels, arrested cells would have half the DNA of a normal cell because they haven't gone through S phase. • counting chromosomes, arrested cells would be missing some. • determining if the amount of DNA per cell always remains the same rather than doubling during S phase. • determining if a spindle forms but never gets broken apart.

  14. Cancer is a genetic disease • Cancer arises from the accumulation of genetic changes (mutations) • Most cancers have a minimum of 6-9 different genes mutated • Not a hereditary disease – we do not pass on cancer to offspring • We can inherit dispositions (susceptibility) to cancer. BRCA 1 mutation (breast and ovarian cancer) is activated by ATM kinases and targets p53 • Many genes that are mutated in cancer code for proteins that are involved in regulating the cell cycle

  15. Cancer Genes: Cells’ Gas and Breaks • Mutations in oncogenes and tumor suppressor genes (p53) can lead to cancer • An oncogene is a gene that when mutated gains a function or is expressed at abnormally-high levels and as a result contributes to converting a normal cell into a cancer cell. Often cause increase in transcription of genes through kinases. Proteins that act in this way are called transcription factors. • A tumor suppressor gene encodes for a protein that is involved in suppressing cell division (p53, or other checkpoint proteins). When mutated it is no longer functional.

  16. Proteins (Gas) involved in the cell cycle • Protein complexes • Cyclins • Cyclin Dependent Kinases (Cdks) • Cdk levels are pretty stable, but Cyclin levels change throughout cell cycle. Ability to drive through the checkpoint are reliant on cyclins and Cdks (oncogenes).

  17. Proteins (Gas) involved in the cell cycle Cdks must bind the correct cyclin in order to function Acts as kinases (enzymes that add phosphate groups to proteins to convert them from an “off” to an “on” state.) Cause cascade of kinases adding phosphates to other proteins to activate them, that eventually leads to transcription of genes (transcription factors). ATP ADP

  18. Regulation of cell cycle G1cyclinE G1 G1 Cdk2 M-Phase Promoting Factor S-Phase Promoting Factor G2 S = Cdk = cyclin

  19. Clicker Question 5 Mis-regulation of the cell cycle occurs when this process is disrupted. For example,what would happen if one of the cyclins were not degraded? • Cell would stop the cell cycle at G1. • Cell would continue through into the next phase without being stopped by checkpoints. http://biology.kenyon.edu/courses/biol114/Chap07/CellCycle2.gif

  20. Clicker Question 6 Inhibitors of Cell Growth Chemotherapy http://www.cbp.pitt.edu/faculty/yong_wan/images/main_cell_cycle.jpg SPRYCEL – Leukemia Tyrosine kinase inhibitor acts in cells by degrading (G1) E cyclins What would happen to cells treated with SPRYCEL? Cells cannot proceed through G1 into S. Cells will proceed through G1 into S without checkpoints. Cells cannot divide.

  21. Clicker Question 7 DNA Duplication Chemotherapy Inhibitors of DNA Duplication Chemotherapy • Anthracyclines antibiotics: chemotherapy derived from bacterium Streptomyces peucetius var. caesius used to treat leukemias, lymphomas, and breast, uterine, ovarian, and lung cancers. Work by intercalating between base pairs thus preventing the replication of rapidly-growing cancer cells. • Anthracylines block the cell cycle at what stage? • G1 • S • G2 • M

  22. Chromosomal Separation– Mitosis Clicker Question 8 Why does it take cells so much longer to line up their chromosomes than it does to separate them? They have to duplicate DNA before separation can occur. They have to coil up DNA before separation can occur. Checkpoint proteins block division until all chromosomes are aligned

  23. Chromosomal Separation– Mitosis Blue: DNA Green: Spindle proteins Assembled & Dissembled During M-phase http://www.cbp.pitt.edu/faculty/yong_wan/images/main_cell_cycle.jpg

  24. Chromosomal Separation– Mitosis anaphase prometaphase metaphase Mitotic spindle – attaches to kinetochores, helps align chromosomes and then separates them. MAD and BUB – part of the spindle checkpoint that halt the cell cycle until all chromosomes are aligned at the middle of the cell. http://www.cbp.pitt.edu/faculty/yong_wan/images/main_cell_cycle.jpg

  25. Clicker Question 9 What would happen if a MAD or BUB protein were damaged or not expressed? The cell would not form the spindle. The cell would be unable to complete cell division. The cell would divide even if the chromosomes were not lined up, resulting in cells with too many or too few chromosomes. The cell would have to repair the damage to the chromosomes before it could proceed to cell division. anaphase prometaphase metaphase

  26. Clicker Question 10 DNA Duplication Chemotherapy Inhibitors of Cell Division Chemotherapy • Taxol: chemotherapy derived from Pacific Yew Tree, Taxus brevifolia, is used to treat lung, ovarian, breast, head and neck cancer, and advanced forms of Kaposi's sarcoma. Taxol works by preventing microtubules from being broken apart. Would a patient with a mutation in the BUD or MAB checkpoint protein respond to Taxol treatment to halt the division of their tumor? • Yes • No

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