Oncogenes and Tumour suppressor genes Flashcards
proto-oncogenes
Where a gain-of-function mutation can drive a cell towards cancer
- mutant, overactive or over-expressed forms of these genes are called oncogenes
Tumour-suppressor genes
Where loss of function mutation(s) can contribute towards cancer. Example - TP53
Loss of function
generally refers to the tumour suppressor genes, where loss of function leads towards cancer development
Gain of function
generally refers to a situation where gain of function leads towards cancer development. For example, where proto-oncogenes are mutated, overactive or over-expressed (now called oncogenes)
loss of p53 by targeted degradation
HPV encodes protein that activates a specific E3 enzyme
Ubiquitin
Is a protein TAG that is attached to a protein that targets it for degradation
retinoblastoma
- a rare childhood tumour in the neural precursor cells of the retina
- It can be hereditary, but not always
- the Rb gene encodes the Rb protein, a key, universal suppressor of cell cycle progression
what are the types of over activity?
1) Deletion or point mutation in coding sequence -> normal amounts of hyperactive protein
2) Mutation in the regulatory region of the gene -> normal protein overproduced
3) Gene amplification -> normal protein greatly overproduced
4) Chromosome rearrangement - changes to regulatory region -> normal protein overproduced or alters the protein coding region causing transcribed gene -> hyperactive protein
Ras
- proteins are normal monomeric GTPases that help transmit signals from cell surface receptors into the cell
- Ras oncogenes isolated from human tumours contain point mutations creating a Ras protein that cannot shut itself off
Therapeutic drug design
Oncogene Products have been used as targets for drug design
1. Monoclonal antibodies to indirectly target cell surface
receptors e.g. Bevacizumab (Avastin) against VEGF (colorectal
cancer, non small cell lung carcinoma (NSCLC), renal cell
carcinoma, glioblastoma)
2. Fusion Proteins e.g. Afilbercept (Zaltrap) block the cell
surface receptor for VEGF (colorectal cancer)
3. Small Molecules e.g. target EGFR with Gefitinib (Iressa)
targets the tyrosine kinase of the receptor (NSCLC)