A signal transducer and cancer Neurofibromin, ras, and cancer - utah.

• 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

Fig. 20.9

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

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)

• 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 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

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

• Sarcomas; rare – tumors of connective tissues and muscle

• Leukemias and lymphomas; 8%of tumors. 

Basal cell carcinoma

Kaposi’s sarcoma of blood vessels leukemia Hodkins lymphoma in lymph node