Oncogenes 1

Question 1

Which oncogenes lead to oncogenic transformation?

Answer 1

Gain of function:

c-erbB2, Ras, P13-K, Mye

Question 2

Which tumor suppressors lead to oncogenic transformation?

Answer 2

Loss of function:

p53, Rb, APC

Question 3

What cause’s tumour’s heterogeneity?

Answer 3

Clonal selection and expansion of cells with growth advantages

Question 4

Multistage model of tumorigenesis

Answer 4

1. Mutation inactivates suppressor gene
2. Cells proliferate and benign tumour cells grow only locally and can’t spread by invasion or metastasis
3. Mutations inactivate DNA repair genes -> malignant cells invade neighbouring tissues, enter blood vessels and metastasise to different sites
4. Proto-oncogenes mutate to oncogenes
5. Further mutations and instability

Question 5

Oncogene

Answer 5

a gene that can induce cancer formation when it is activated by mutations or overexpression

Question 6

A proto-oncogene is

Answer 6

a normal gene, before it was mutated.

-> highly conserved in sequence throughout the evolution between different species

Question 7

Oncogenic viruses possess

Answer 7

Genetic material that causes malignant transformation of infected cells

Question 8

c-Src

Answer 8

present in mammalian cells in the form of proto-oncogene

Question 9

Outline metastasis

Answer 9

1. Transformation
2. Angiogenesis
3. Motility & invasion
4. Embolision & circulation
   - multi-cell aggregates, lymphocytes, platelets
5. Arrest in capillary beds
6. Adherence
7. Extravasation into organ parenchyma
8. Response to environment
9. Tumour cell proliferation and angiogenesis
10. Metastasis with metastases of metastasis

Question 10

How do chemical carcinogens lead to malignancy?

Answer 10

Repair system failure -> apoptosis

Question 11

How does harmful radiation lead to malignancy?

Answer 11

Breaks DNA

Question 12

How do tumerogenic viruses lead to malignancy?

Answer 12

These can induce malignant transformation upon cellular infection. As they integrate into the host cell’s genome, they remove parts of the host’s DNA and pack into the virus’ head. Viruses do NOT have repair mechanisms and oncogenic mutations would accumulate, with no way to fix them.

Question 13

The molecular mechanism of DNA repair usually involves

Answer 13

homologous and non-homologous recombination and single nucleotide repair

Question 14

What do mutations do to oncogenes?

Answer 14

Induce gains in function and proliferation

-> constitutive activation pushing the cell cycle with no control mechanisms

Question 15

Mutations in tumor-supressor genes cause

Answer 15

alter the molecular mechanisms by which the cell cycle is stopped and regulated, letting go on without regulation.

Question 16

In a five stage process, there are four events that can turn a normal cell into a malignant cell:

Answer 16

1. Ras / PI3K - mutations in Ras and PI3K are gain of function mutations since Ras induces proliferation and PI3K mediates pro-survival signalling.
2. Telomerase - overexpression of this molecule alters the process in which telomeres are shortened during every mitotic division by extending the telomeres and allows cells to divide more than they normally would.
3. p53 / Rb - loss of function in these tumor suppressor genes that are responsible for the stopping the cell cycle at particular moments in time
4. E-Cadherin / RhoC - these molecules are involved in invasion and cell motility, and mutations in these would allow the cell to have access to the body’s vascular system.
   - Overexpression of matrix metalloproteinases allows cancer cell proliferation.
   - Small GTPases from the Rho family allows them to acquire sufficient motility to move.

Question 17

Classes of Oncogenes

Answer 17

1. Extracellular growth factors
2. Transmembrane molecules like growth factor receptors
3. Membrane associated molecules
4. Cytoskeleton associated mutations
5. Cytosolic second messengers

Question 18

How does the product of the sis oncogene of SSV act as an example of a proto-oncogene in a signal transduction pathway?

Answer 18

1. Infection by SSV
2. Integration of viral DNA into cell’s genome
3. Expression and secretion of sis oncogene
   - > viral infection leads to constituitive secretion of sis, activation of PDGF-R as product is a PDGF-like growth factor
4. Induction of growth and proliferation

Question 19

How does the product of the erB oncogene change EGF-R

Answer 19

The infection removes the ligand-binding domain from the receptor, and the loss of this and of a 22 amino acid at the C-terminus (the autoinhibitory domain) produces an activated form of this receptor tyrosine kinase.

Question 20

What are the consequences of the erB oncogene?

Answer 20

1.Constitutive mitogenic signal to the nucleus in the absence of the ligand (EGF).
2. Continuous stimulation of proliferation.
Overexpression occurs through:
- Gene amplification
- Increased expression

Question 21

Where is erB found?

Answer 21

Squamous carcinomas, Invasive bladder tumors, glioblastomas

Question 22

Outline c-erB (human) or neu (rat) oncogene

Answer 22

The point-mutation is found in the transmembrane domain of the receptor.

• > This mutation changes the conformation and induces dimerization and cross-phosphorylation of the cytosolic domains of the receptor regardless on whether the ligand is bound to the extracellular domain.
• > Ligand-independent receptor dimerization.