A signal transducer and cancer
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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

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Tumor suppressor genes table 20 3
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
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




Fig. 20.9 1 more in any cell =


Fyi the rb gene
FYI The RB gene 1 more in any cell =

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
Function of normal 1 more in any cell = pRBtumor suppressor protein

pRB is a G1  S checkpoint protein

Allows cell to progress to S phase


How does prb work
How does pRB work? 1 more in any cell =

EF2is a transcription factor that allows genes to be transcribed  S phase

  • pRB bindsEF2

    EF2 cannot bind DNA

    Cell cycle arrested = cell does not move to S

The big picture animation Plattsburgh



3. 1 more in any cell = EF2released to travel into nucleus

Acts as a transcription factor  cell moves to S phase.


Cyclin then degraded (no more phosphorylation of pRB) 1 more in any cell =

EF2 bound to pRB

If RB gene is mutant then 



PCR tyr.


Fyi examples of hereditary cancers predisposition genes
FYI: Examples of hereditary cancers (predisposition genes) tyr.

  • 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. Tumorsuppressor, chromosome 17.


Cancer multi step disease
Cancer: multi-step disease tyr.

  • Accumulation of mutations in a number of genes in single cell

  • Can build up over decades

  • Vogelstein model

    • FAP colorectal cancer



FAP tyr.

  • 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
p53 tyr. tumor suppressor

  • Involved in ~50% of cancers


Role of p53 tumor suppressor
Role of tyr. 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
Damage DNA tyr.  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
p53 can activate apoptosis pathway eliminated by apoptosis (A). Cancer cells avoid apoptosis and continue to multiply in an unregulated manner (B).

Apoptosis

  • Programmed cell death

    HeLa cell apoptosis

    OR

    Garland science


  • p53/p53 knockout mice eliminated by apoptosis (A). Cancer cells avoid apoptosis and continue to multiply in an unregulated manner (B).

    • Develop normally, within 10 months 100% of mice have cancer


Example of tp53 gene hereditary cancer
Example of TP53 gene hereditary cancer eliminated by apoptosis (A). Cancer cells avoid apoptosis and continue to multiply in an unregulated manner (B).

  • 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
Evidence that p53 is a tumor suppressor eliminated by apoptosis (A). Cancer cells avoid apoptosis and continue to multiply in an unregulated manner (B).

  • Moshe Oren

  • Weizmann Institute/Israel


Angiogenesis
angiogenesis eliminated by apoptosis (A). Cancer cells avoid apoptosis and continue to multiply in an unregulated manner (B).

  • Tumor obtains its own blood supply

  • HHMI animation


Metastasis
metastasis eliminated by apoptosis (A). Cancer cells avoid apoptosis and continue to multiply in an unregulated manner (B).

  • Tumor cells move to new location

    metastasis

Pancreatic cancer  liver


Telomerase in cancer cells
Telomerase in cancer cells eliminated by apoptosis (A). Cancer cells avoid apoptosis and continue to multiply in an unregulated manner (B).

  • Telomeres at ends of chromosomes

  • Chromosome shortens with each cell division

  • No telomerase in normal cells

  • Cancer cells make telomerase  immortalized


Types of cancer
Types of cancer eliminated by apoptosis (A). Cancer cells avoid apoptosis and continue to multiply in an unregulated manner (B).

  • 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


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