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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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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.
why do we care about cancer
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
cell division one part of the cell cycle
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)
fighting cancer

Clicker Question 1

Fighting Cancer
  • Death rates are lower since 1980 for all of the following female cancers, EXCEPT:
    • Breast
    • Lung
    • Colorectal
    • Uterus
chemotherapy treatments
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?

group assignment part 1
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

group assignment part 2
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 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.
group assignment part 3
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?

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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

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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.
cancer is a genetic disease
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
cancer genes cells gas and breaks
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.
proteins gas involved in the cell cycle
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).
proteins gas involved in the cell cycle1
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

regulation of cell cycle
Regulation of cell cycle

G1cyclinE

G1

G1 Cdk2

M-Phase

Promoting

Factor

S-Phase

Promoting

Factor

G2

S

= Cdk

= cyclin

slide19

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

inhibitors of cell growth chemotherapy

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.

slide21

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
chromosomal separation mitosis
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/main_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/main_cell_cycle.jpg

slide25

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

slide26

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