F2: Oncogenes Flashcards
What are the genes that have been identified to play a major role in development and progression of cancer?
Three classes of genes:
- Oncogenes: genes that promote cancer
- Tumour suppressor genes: Genes that act to prevent cancer
- Mismatch repair genes: genes that repair mutated DNA
Oncogenes
what are they
what needs to happen to predispose to cancer
- Oncogenes are altered forms of normal cellular genes that promote cell growth.
- in the mutant form these gene products signal to cells to divide inappropriately and promotes cell growth in inappropriate circumstances
- Requires a mutation in only one copy of the gene but the mutation must lead to an increased function of the oncogene product for cancer predisposition to occur.
What are proto-oncogenes ? what are they important for?
Proto-oncogenes are normal cellular genes that are important in promoting cell growth and cell division
Extremely important, essential, for normal cell survival, growth development and differentiation
oncogenes are altered forms of proto-oncogenes that lead to increased activity of these gene products and can cause cancer.
What are the major classes of proto-oncogenes?
- growth factors
- growth factor receptors
- intracellular signalling proteins
- transcription factors
- cell cycle control proteins
These are essential in cell cycle, growth and promoting differentiation and cell survival
oncogenic change results in INCREASE ACTIVITY
What are the three main ways a proto-oncogene can become an oncogene
- An activating mutation in a DNA coding sequence
A deletion or point mutation in coding sequence = hyperactive protein made in normal amounts
e.g Ras - Gene amplification (e.g. brain cancers, breast cancer)
normal protein greatly overproduced
EGFR-2 (also known as HER2)
critical receptor involved in cell growth pathways, often over expressed in cancers. - Chromosomal translocation: (seen in greater than 90% of leukemias and in many lymphomas)
- Gene can be placed nearby a DNA sequence causes normal protein to be overproduced.
- gene can be fused to actively transcribe gene. greatly overproduces fusion protein.
or fusion protein may be hyperactive
Give examples of what some proto-oncogenes code for and what happens to them in cancer
- Some proto-oncogenes code for growth factors to stimulate cell division. In cancer, mutations can cause overproduction of these growth factors.
- Some proto-oncogenes code for growth factor receptors to stimulate cell division.
In cancer, a mutant receptor may no longer need growth factor binding to stimulate cell division. - Some proto-oncogenes code for proteins that participate in the transduction of signals for cell division (signally proteins)
In cancer these are mutated so that they no longer need an external stimulis and signal cell division constantly. - Some proto-oncogenes code for transcription factors that can activate genes involved in cell division.
In cancer, mutant transcription factors always bind to their target gene promoter.
What was the first animal virus to be implicated in cancer
Rous sarcoma virus - a retro-virus which carries an oncogene that causes cancer
What are the role of viruses in cancer development?
A RNA or retro-virus can transform a host genome from proto-oncogene to oncogene. (human T-cell leukemia)
The proto-oncogene may be altered folloing insertion of the viral gene either upstream of the proto-oncogene or within the coding sequence.
The protein may have increased activity resulting from an insertional mutation. The protein may be overexpressed due to activation of a promoter sequence.
DNA viruses: Activate the host replication machinery –> Herpes Virus, Papilloma virus
What is an important group of signally proteins ?
Tyrosine kinases, become more active in cancers.
Tyrosine kinases initiate an intracellular cascade of signals to regulate cellular proliferation, survival, differentiation, function and motility.
What are some oncogenes involved in human cancers?
Genes encoding for growth factors or their receptors:
PDGF - involved in brain cancer
Erb-B (EGFR) - involved in brain and breast cancer
Genes encoding in cell signalling.
K-ras: involved in lung, ovarian, colon and pancreatic cancers
N-ras - involved in leukemias
Gene for transcription factors that activate genes.
c-myc –> involved in leukemias, breast, stomach, and lung
N-myc–> involved in neuroblastoma and glioblastoma
L-myc –> invovled in lung cancer
Cancer treatment? what are the three main types and what do they involve;
- Chemotherapy - mix of toxic compounds aims to kill most rapidly dividing cells - therefore will kill cancer cells plus normal cells that divide rapidly (i.e bone marrow, gut) therefore high dose chemotherapy associated with significant side effects
- Surgery - cut the cancer out, not always possible - e.g cancer could be in brain
- Targeted therapies: find out what the molecular changes in the cancer are and design therapies that target the molecular rearrangement.
Tyrosine kinases can be inhibited pharmacologically through multiple mechanisms.
- ATP competitive inhibitors: directly inhibit the catalytic activity of the kinase by interfering with the binding of ATP or substrates. (&slow the growth of these cancer cells. If stop ATP binding can stop the overactivity of these RTK)
- antibodies against receptor tyrosine kinases or their ligands.
- so can interrupt kinase activation signalling through neturalization of ligand.
- block ligand binding, receptor internalisation, perhaps antibody-mediated cytotoxicity - e.g breast cancer: EGFR targeted therapy - HER2 - Anti-angiogenics
As angiogenesis is a major event in cancer growth and proliferation, tyrosine kinase inhibitors as a target for anti-angiogenesis can be aptly applied as a new mode of cancer. i.e VEGF - vascular endothelial growth factor
