1. 34 Cancer

2. Lecture Outline, 11/30/05 Review the Cell cycle
Cancer is a genetic disease
Oncogenes and proto-oncogenes
Normally promote cell growth.
Become oncogenic after point mutations, duplications, deletion of silencer, etc
Tumor Suppressor genes
Normally inhibit cell growth.
Allow cell growth when damaged or deleted.
Mutator genes
The multi-step model of cancer

3. Cancer is caused by mutant genes
Mutations in regulatory genes lead to uncontrolled cell growth
Understanding gene regulation is one key to understanding cancer
All cancers trace back to single cell
Must accumulate multiple mutations, all in the same cell lineage

4. Changes in growth properties of cancer cells

5. The incidence of human cancers increases markedly with age
It takes a long time for the causative mutations to accumulate in a cell

6. The Human Cell Cycle
~ 1 hour
~ 4 hours
~ 10 hours
~ 9 hours

7. Cell Cycle Regulators and Cancer

8. Free E2F is a transcription activator
Rb represses E2F
Cyclin/Cdk inactivates Rb by phosphorylation

9. P53 is a transcription factor that activates p21, an inhibitor of cyclin/cdk2

10. Signaling pathways that regulate cell division1
Growth
factor 2
Receptor p
GTP
Ras 3
G protein
Hyperactive
Ras protein
(product of
oncogene)
issues signals
on its own 4
Protein kinases
(phosphorylation
cascade) 5
Transcription
factor (activator)
NUCLEUS
DNA
Gene expression
Protein that
stimulates
the cell cycle UV
light
DNA damage
in genome 1
Active
form
of p53
Defective or
missing
transcription
factor, such as
p53, cannot
activate
MUTATION
inhibits
EFFECTS OF MUTATIONS
Protein
overexpressed
Cell cycle
overstimulated
Increased cell
division
Cell cycle not
inhibited
Protein absent
(a) Cell cycle–stimulating pathway.
This pathway is triggered by a growth
factor that binds to its receptor in the
plasma membrane. The signal is relayed to
a G protein called Ras. Like all G proteins, Ras
is active when GTP is bound to it. Ras passes
the signal to a series of protein kinases.
The last kinase activates a transcription
activator that turns on one or more genes
for proteins that stimulate the cell cycle. If a
mutation makes Ras or any other pathway
component abnormally active, excessive cell
division and cancer may result.
(b) Cell cycle–inhibiting pathway. In this
pathway, DNA damage is an intracellular
signal that is passed via protein kinases
and leads to activation of p53. Activated
p53 promotes transcription of the gene for a
protein that inhibits the cell cycle. The
resulting suppression of cell division ensures
that the damaged DNA is not replicated.
Mutations causing deficiencies in any
pathway component can contribute to the
development of cancer.
(c) Effects of mutations. Increased cell division,
possibly leading to cancer, can result if the
cell cycle is overstimulated, as in (a), or not
inhibited when it normally would be, as in (b).
MUTATION
Figure 19.12

11. Stimulation versus inhibition of G1 progression
Stimulation of G1 progression
Inhibition of G1 progression
mitogens
DNA-damage
anti-mitogen (TGF-b)
myc
ras
PKB
p53
p15 ?
cyclin D / cdk4
p27
p21
cyclin D / cdk4
p16 P P
pRB
pRB
pRB
pRB P P P P
Inhibition
S-phase entry
Inhibition
S-phase entry
S-phase entry
allowed
S-phase entry
allowed
oncogenes
tumor suppressor genes

12. Oncogenes
All are involved in positive control of cell growth and division.
About 100 different oncogenes have been identified
Can be various kinds of proteins:
Growth factors, regulatory genes involved in the control of cell multiplication.
Protein kinases, add phosphate groups to target proteins, important in signal transduction pathways.
“Proto-oncogenes”
Normal form of the gene that is involved in positive regulation of the cell cycle

13. Genetic changes that can turn proto-oncogenes into oncogenes
DNA
Translocation or transposition:
gene moved to new locus,
under new controls
Gene amplification
Point mutation
within a control
element
within the gene
Oncogene
Normal growth-stimulating
protein in excess
Hyperactive or
degradation-
resistant protein
New
promoter
Figure 19.11

14. Translocation puts abl under the control of a different promoter

15. Translocation puts bcl near a new enhancer

16. Ras Proto-oncogene Mutated in 30% of all cancers.
A “molecular switch” in the signal transduction pathway leading from growth factors to gene expression controlling cell proliferation:
GF  receptor   Ras    TF  target genes  growth.
A single amino acid change in Ras protein can cause constant stimulation of the pathway, even in the absence of growth factors.

17. Receptor tyrosine kinases can activate ras
ras is a monomeric G-protein
“molecular switch”
You’ve seen RAS before . . .

18. Mitogen Activated Protein Kinases MAPKs
Ras activation sets off a phosphorylation cascade
Mitogen
Activated
Protein
Kinases
MAPKs 10
100
MAPKKK
MAPKK
1,000
Controls:
-Transcription
Factors
-Translation
-Cell Division
MAPK
100,000

19. - broken ras – won’t shut off
PROBLEMS IN CANCER:
- broken ras – won’t shut off
Broken receptor – thinks ligand there
even when it isn’t
broken MAPK – on all the time, even when
not phosphorylated
RESULT: continuous signal for cell to divide

20. Oncogenes act cooperatively in tumor-induction

21. Tumor Suppressor Genes
Normally inhibit cell growth
Example: retinoblastoma
RB protein normally blocks a transcription factor, E2F

23. p53 Gene Detects DNA damage The “Last Gatekeeper”
Involved in 50% of cancers
Often not malignant despite other cancer-causing mutations until p53 is inactivated by mutation.
Two possible responses to DNA damage:
1) Acts as a Transcription Factor to activate expression of p21, which inhibits CDK/G1 cyclin to halt the cell cycle; then activates DNA repair.
2) Triggers Apoptosis (programmed cell death) if damage can’t be repaied.

24. Apoptosis = controlled cell death
“executioner” proteins (caspases) break down the cell
Reduced cell death can also lead to cancer

25. Apoptosis pathways

27. Mutator genes
Cancer is caused by mutations, so factors that increase mutation rate will increase cancer rate.
What kinds of genes would increase mutation rate?
Example: BRCA1 and BRCA2
Many environmental factors (carcinogens) also cause DNA damage or mutations, that can lead to cancer

28. A multistep model for the development of colorectal cancer
(1) The clonal origin of tumors: each individual cancer is a clone that arises from a single cell.
The progeny cells have growth advantage over the surrounding normal cells.
Colon
(2) Cancer development is a multi-step process. Multiple mutations accumulated over periods of many years ----“multi-hit” model.
1 Loss of
tumor-suppressor
gene APC (or
other)
2 Activation of
Ras oncogene
4 Loss of
tumor-suppressor
gene p53
Colon wall
3 Loss of
tumor-
suppressor
gene DCC
5 Additional
mutations
Normal colon
epithelial cells
Small benign
growth (polyp)
Larger benign
growth (adenoma)
Malignant tumor
(carcinoma)
Figure 19.13