http://www.youtube.com/watch?v=Q6ucKWIIFmg&feature=related
Cell Cycle, Cancer, & Chemotherapy
Learning Objectives:
1.
2.
3.
4.
5.
6.
7.
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?
– 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
Cancer: Unregulated Cell Division
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)
Clicker
Question
Fighting
Cancer 1
Death rates are
lower since 1980 for
all of the following
female cancers,
EXCEPT:
A. Breast
B. Lung
C. Colorectal
D. Uterus
Chemotherapy Treatments
Work at various stages to stop an overactive cell
cycle
1. Inhibitors of Cell Growth (Growth Factor
Proteins e.g. hormones)
2. Inhibitors of DNA Duplication
3. Inhibitors of Cell Division
Where, when, and how do they work?
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
Cell Division
Chromosome Separation
Cell Growth 2
Cell Growth 1
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
Clicker Question 2
What would happen if the cell cycle proceeded
normally, except that cell division did not
occur?
A. The cell growth phases would become shorter.
B. The separation of chromosomes couldn’t occur.
C. The resulting cells would get smaller and
smaller.
D. Cells without nuclei would be formed.
E. A large cell with multiple nuclei would result.
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 Cell Size Big Enough?
1.
DNA undamaged before copying?
2. All Chromosomes Attached
2
to spindle and aligned?
3. All Genetic Material Duplicated? Environment Favorable?
3
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?
A.
B.
C.
D.
II, 3; III, 2; IV, 1
II, 1; III, 2; IV, 3
I, 1; II, 3; IV, 2
II, 1; III, 3, IV, 2
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:
A. comparing DNA levels, arrested cells would have half the DNA
of a normal cell because they haven't gone through S phase.
B. counting chromosomes, arrested cells would be missing some.
C. determining if the amount of DNA per cell always remains the
same rather than doubling during S phase.
D. determining if a spindle forms but never gets broken apart.
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
• 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
• 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
cycle
ATP
ADP
• 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).
Regulation of cell cycle
G1
M-Phase
Promoting
Factor
G2
G1cyclinE
S-Phase
Promoting
Factor
G1 Cdk2
S
= cyclin
= Cdk
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?
A. Cell would stop the cell cycle
at G1.
B. Cell would continue through
into the next phase without
being stopped by
checkpoints.
http://biology.kenyon.edu/courses/biol114/Chap07/CellCycle2.gif
Clicker Question 6
Inhibitors of Cell Growth Chemotherapy
SPRYCEL – Leukemia
Tyrosine kinase inhibitor
acts in cells by
degrading (G1) E
cyclins
What would happen to
cells treated with
SPRYCEL?
A. Cells cannot proceed
through G1 into S.
B. Cells will proceed
through G1 into S
without checkpoints.
C. Cells cannot divide.
http://www.cbp.pitt.edu/faculty/yong_wan/images/main_cell_cycle.jpg
Question
7
DNAClicker
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?
A.G1
B.S
C.G2
D.M
Clicker Question 8
Chromosomal Separation– Mitosis
Why does it take cells so much
longer to line up their
chromosomes than it does to
separate them?
A. They have to duplicate DNA
before separation can occur.
B. They have to coil up DNA before
separation can occur.
C. Checkpoint proteins block
division until all chromosomes
are aligned
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
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
Clicker Question 9
What would happen if a MAD or BUB protein were
anaphase
damaged or not expressed?
A. The prometaphase
cell would not form the spindle.
B. The cell would be unable to complete cell division.
C. The cell would divide even if the chromosomes
metaphase
were not lined up, resulting in cells with too many
or too few chromosomes.
D. The cell would have to repair the damage to the
chromosomes before it could proceed to cell
division.
Question
10
DNAClicker
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?
A. Yes
B. No