Oncogenes 1 Flashcards
Which oncogenes lead to oncogenic transformation?
Gain of function:
c-erbB2, Ras, P13-K, Mye
Which tumor suppressors lead to oncogenic transformation?
Loss of function:
p53, Rb, APC
What cause’s tumour’s heterogeneity?
Clonal selection and expansion of cells with growth advantages
Multistage model of tumorigenesis
- Mutation inactivates suppressor gene
- Cells proliferate and benign tumour cells grow only locally and can’t spread by invasion or metastasis
- Mutations inactivate DNA repair genes -> malignant cells invade neighbouring tissues, enter blood vessels and metastasise to different sites
- Proto-oncogenes mutate to oncogenes
- Further mutations and instability
Oncogene
a gene that can induce cancer formation when it is activated by mutations or overexpression
A proto-oncogene is
a normal gene, before it was mutated.
-> highly conserved in sequence throughout the evolution between different species
Oncogenic viruses possess
Genetic material that causes malignant transformation of infected cells
c-Src
present in mammalian cells in the form of proto-oncogene
Outline metastasis
- Transformation
- Angiogenesis
- Motility & invasion
- Embolision & circulation
- multi-cell aggregates, lymphocytes, platelets - Arrest in capillary beds
- Adherence
- Extravasation into organ parenchyma
- Response to environment
- Tumour cell proliferation and angiogenesis
- Metastasis with metastases of metastasis
How do chemical carcinogens lead to malignancy?
Repair system failure -> apoptosis
How does harmful radiation lead to malignancy?
Breaks DNA
How do tumerogenic viruses lead to malignancy?
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.
The molecular mechanism of DNA repair usually involves
homologous and non-homologous recombination and single nucleotide repair
What do mutations do to oncogenes?
Induce gains in function and proliferation
-> constitutive activation pushing the cell cycle with no control mechanisms
Mutations in tumor-supressor genes cause
alter the molecular mechanisms by which the cell cycle is stopped and regulated, letting go on without regulation.
In a five stage process, there are four events that can turn a normal cell into a malignant cell:
- Ras / PI3K - mutations in Ras and PI3K are gain of function mutations since Ras induces proliferation and PI3K mediates pro-survival signalling.
- 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.
- p53 / Rb - loss of function in these tumor suppressor genes that are responsible for the stopping the cell cycle at particular moments in time
- 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.
Classes of Oncogenes
- Extracellular growth factors
- Transmembrane molecules like growth factor receptors
- Membrane associated molecules
- Cytoskeleton associated mutations
- Cytosolic second messengers
How does the product of the sis oncogene of SSV act as an example of a proto-oncogene in a signal transduction pathway?
- Infection by SSV
- Integration of viral DNA into cell’s genome
- 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 - Induction of growth and proliferation
How does the product of the erB oncogene change EGF-R
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.
What are the consequences of the erB oncogene?
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
Where is erB found?
Squamous carcinomas, Invasive bladder tumors, glioblastomas
Outline c-erB (human) or neu (rat) oncogene
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.
