Download Tumor suppressor

• A signal transducer and cancer
Neurofibromin, ras, and cancer - utah
Tumor suppressor genes Table 20.3
• Protein products suppress uncontrolled cell
proliferation
• Both copies must be inactivated for loss of
function = 2 mutations in one cell required
• Recessive
• 2 hit model (Knudson 1971)
Example
• Retinoblastoma
– Eye cancer develops in childhood
– Hereditary OR Sporadic – one eye only
(13q14.1-q14.2.)
11 cases per million children aged 1 – 4 in US/yr treat with laser therapy
• Sporadic – develop 2 mutations in 1 cell in 1 eye
after birth
Child born RB/RB in all cells  RB/rb in one cell
• Hereditary – inherited 1 mutation in all body cells,
need 1 more in any cell = Loss of
heterozygosity (LOS)
Child born RB/rb in all cells  rb/rb in one cell
Fig. 20.9
FYI The RB gene
180 kb  2.7 kb mRNA encodes pRB
encodes 928 aa nuclear protein
• 27 exons, largest is 200 bp
• Many mutations found
– Promoter, exons, splice sites
– Point, frameshift, nonsense, missense
Function of normal pRB tumor suppressor
protein
pRB is a G1  S checkpoint protein
Allows cell to progress to S phase
How does pRB work?
EF2 is a transcription factor that allows
genes to be transcribed  S phase
1. pRB binds EF2
EF2 cannot bind DNA
Cell cycle arrested = cell does not move to S
The big picture animation Plattsburgh
2. A Cyclin/CDK then phosphorylates
pRB
3. EF2 released to travel into nucleus
Acts as a transcription factor  cell moves
to S phase.
Cyclin then degraded (no more
phosphorylation of pRB)
EF2 bound to pRB
If RB gene is mutant then 
Parent with high RB risk. Mutation changes amino acid his to tyr.
GGTGATC
vs
GGTAATC
Exon 18.
PCR
FYI: Examples of hereditary cancers (predisposition genes)
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Breast-ovarian cancer syndrome 1 BRCA1 gene. 80 %lifetime chance of
developing breast cancer and 60 percent lifetime chance of ovarian cancer. Tumor
suppressor, chromosome 17
Breast-ovarian cancer syndrome 2 BRCA2 gene. 80 % lifetime chance of
developing breast cancer and a 20 percent lifetime chance for ovarian cancer.
Tumor suppressor, chromosome 13
Familial adenomatous polyposis hereditary colon cancer. APC gene. Individuals
develop hundreds to thousands of polyps. Tumor suppressor, chromosome 5
Familial melanoma increased chance of developing melanoma and may have an
increased chance for pancreatic and brain tumors. A CKD inhibitor.
Hereditary nonpolyposis colon cancer (HNPCC) hereditary colon cancer
resulting from an change in one of at least four genes. 80 % lifetime risk of colon
cancer. Female family members have a 40 %to 60 % lifetime risk of developing
uterine cancer. DNA repair
Von Hippel Lindau (VHL) syndrome VHL gene. increased risk of kidney cancer,
tumors of adrenal gland, retina, and brain and spinal tumors. Tumor suppressor,
chromosome 3.
Li Fraumeni - TP53 gene many cancers. Tumor suppressor, chromosome 17.
Cancer: multi-step disease
• Accumulation of mutations in a number of
genes in single cell
• Can build up over decades
• Vogelstein model
– FAP colorectal cancer
Colorectal cancer
FAP
APC tumor suppressor gene
mutation is inherited
(adenoma class I is benign tumor)
Mutation in Ras Oncogene
Mutation in Tumor suppressor
gene DCC
(Adenoma class III)
 mutation in Tumor suppressor
gene TP53
metastasis
p53 tumor suppressor
• Involved in ~50% of cancers
Role of p53 tumor suppressor
• Monitors signals that indicate DNA
damage/mutation
• Damage cell  increase p53 protein
•
Normal cell  p53 would inhibit cell growth but p53 has short half life
Damage DNA  p53  DNA repair, cell
cycle arrest or apoptosis  genome integrity
When normal cells are damaged beyond
repair, they are eliminated by apoptosis
(A). Cancer cells avoid apoptosis and
continue to multiply in an unregulated
manner (B).
p53 can activate apoptosis pathway
Apoptosis
– Programmed cell death
HeLa cell apoptosis
OR
Garland science
• p53/p53 knockout mice
– Develop normally, within 10 months 100% of
mice have cancer
Example of TP53 gene
hereditary cancer
• Li-Fraumeni syndrome
– Inherit one mutant copy of TP53 gene
– One more mutation (single cell)…..
– Develop a number of cancers
• Bone, Blood cell, Brain, Breast, Colon, Bladder cancer
– >90% lifetime risk of cancer
– (Very rare, 17p13.1)
Evidence that p53 is a tumor
suppressor
• Moshe Oren
• Weizmann Institute/Israel
angiogenesis
• Tumor obtains its own blood supply
• HHMI animation
metastasis
• Tumor cells move to new location
metastasis
Pancreatic cancer  liver
Telomerase in cancer cells
• Telomeres at ends of chromosomes
• Chromosome shortens with each cell
division
• No telomerase in normal cells
• Cancer cells make telomerase 
immortalized
Types of cancer
• Carcinomas; 90% of cancers
– epithelial cells
Basal cell carcinoma
• Sarcomas; rare
– tumors of connective tissues and muscle
• Leukemias and lymphomas; 8%
of tumors.
Kaposi’s sarcoma of blood vessels
leukemia
Hodkins lymphoma in lymph node