Cell Cycle, Mitosis, Cancer

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http//www.youtube.com/watch?vQ6ucKWIIFmgfeature
related
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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.

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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

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Cancer Unregulated Cell Division
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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 arent supposed to.
• Cells divide in a place they arent supposed to.
• Need to understand how the cell is coordinating
  this process
• Understanding can lead to cancer treatments
  (chemotherapy)

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Fighting Cancer
Clicker Question 1

• Death rates are lower since 1980 for all of the
  following female cancers, EXCEPT
• Breast
• Lung
• Colorectal
• Uterus

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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?

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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 1
Cell Growth 2
Cell Division
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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
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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 couldnt occur.
• The resulting cells would get smaller and
  smaller.
• Cells without nuclei would be formed.
• A large cell with multiple nuclei would result.

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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
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2
1. Cell Size Big Enough? DNA undamaged before
copying?
2. All Chromosomes Attached to spindle and
aligned?
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3. All Genetic Material Duplicated? Environment
Favorable?
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Clicker Question 3
Indicate the location of each cell cycle
checkpoint

1. Cell Size Big Enough? DNA undamaged before
   copying?
2. All Chromosomes attached to spindle and aligned?
3. All Genetic Material Duplicated and undamaged?
   Environment Favorable?

IV

1. II, 3 III, 2 IV, 1
2. II, 1 III, 2 IV, 3
3. I, 1 II, 3 IV, 2
4. II, 1 III, 3, IV, 2

II
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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.

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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

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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.

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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).

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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).

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Regulation of cell cycle
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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/C
ellCycle2.gif
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Inhibitors of Cell Growth Chemotherapy
Clicker Question 6

• 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.

• http//www.cbp.pitt.edu/faculty/yong_wan/images/ma
  in_cell_cycle.jpg

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DNA Duplication Chemotherapy
Clicker Question 7
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

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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

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Chromosomal Separation Mitosis
Blue DNA Green Spindle proteins Assembled
Dissembled During M-phase

• http//www.cbp.pitt.edu/faculty/yong_wan/images/ma
  in_cell_cycle.jpg

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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/ma
  in_cell_cycle.jpg

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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
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DNA Duplication Chemotherapy
Clicker Question 10
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