Post on 18-Dec-2015
• 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
11 cases per million children aged 1 – 4 in US/yr treat with laser therapy
(13q14.1-q14.2.)
• 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
FYI The RB gene180 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
FYI: Examples of hereditary cancers (predisposition genes)
• 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
FAP APC tumor suppressor genemutation 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
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
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
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)
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