Oncogenes and Tumour Suppressor Genes Flashcards
What are the six hallmarks of cancer?
Disregard of signals to stop proliferating Disregard of signals to differentiate Capacity for sustained proliferation Evasion of apoptosis Ability to invade Ability to promote angiogenesis
What is Gene amplification?
Production of multiple gene copies
What are chimeric genes?
Chromosomal translocation
Genes that are formed by combinations of portions of one or more coding sequence to produce new genes (e.g. the swapping of tips of chromosomes)
When can the formation of chimeric genes be a problem?
- If one of the pieces of translocated DNA is a promoter, it could lead to upregulation of the other gene portion (this occurs in Burkitt’s lymphoma)
- If the fusion gene codes for an abnormal protein that promotes cancer
What is the Philadelphia Chromosome?
Chromosome produced by the translocation of the ABL gene on chromosome 9 to the BCR gene on chromosome 22
The BCR-ABL fusion gene encodes a protein that promotes the development of cancer
-Example of Insertional Mutagenesis!
State some important oncogenes in human cancers.
SRC – tyrosine kinase Myc – transcription factor JUN – transcription factor Ha-Ras – membrane bound GTPase Ki-Ras – membrane bound GTPase
What is an example of an inherited cancer?
Retinoblastoma – malignant cancer of the developing retinal cells
What mutation causes retinoblastoma?
RB1 gene
13q14
What are the functional classes of tumour suppressor genes?
- Regulate cell proliferation
- Maintain cellular integrity
- Regulate cell growth
- Regulate the cell cycle
- Nuclear transcription factors
- DNA repair proteins
- Cell adhesion molecules
- Cell death regulators
State some important tumour suppressor genes in human cancers
- P53 – cell cycle regulator
- BRCA1 – cell cycle regulator
- PTEN – tyrosine and lipid phosphatase
- APC – cell signalling
In what form is p53 inactive?
When it is bound to MDM2
What is p53 important for?
It is important for regulation of p53 target genes (involved in DNA repair, growth arrest, senescence etc.) and protein-protein interactions (e.g. apoptosis)
What is odd about p53 considering it is a tumour suppressor gene?
It acts in a DOMINANT manner –mutation of a single copy is sufficient to achieve dysregulation of activity
What deletion causes loss of the APC gene?
5q21
What is APC involved in?
Cell adhesion
Cell signalling
What is the risk of people with the APC mutation developing colon cancer?
90%
What signalling pathway is APC involved in?
WNT signalling
What is the main role of APC that prevents uncontrolled growth?
It breaks down beta-catenin so that it doesn’t bind to LEF1 and promote uncontrolled proliferation
Describe the step-by-step development of colorectal cancer.
- APC mutations –> hyperproliferative epithelium
- DNA hypomethylation + K-ras mutation will make the polyps –> adenomas
- P53 mutation will result in the development of carcinoma
- Metastasis
What are the four ways in which a normal photo-oncogene can be activated?
- Mutation in coding sequence
- point mutation or deletion - Gene amplification
- protein may block DNA polymerase so it repeatedly backs up over same area a few times creating many identical genes - Chromosomal Translocation
- chimeric genes - Insertional Mutagenesis
- vial infections, viruses may insert genome into our DNA which is fine as most of our DNA doesn’t code, if inserted into coding region could cause cancer
Give an example of insertional mutagenesis?
Philadelphia chromosome
What class of genes are signal transduction proteins?
Proto-oncogenes
Give an example of a cancer caused by a chromosomal translocation
Burkitt’s Lymphoma
What gene and class is important in Burkitt’s Lymphoma?
MYC, its a transcription factor and class is ONCOGENE
Describe the normal pathway of RAS and explain what happens with mutant RAS
Upon binding GTP, Ras becomes active
This binding allows Ras to bind Raf and deliver signal to Mek and Erk
Dephosphorylation of GTP to GDP unbinds Raf from Ras
Mutant Ras fails to dephosphorakate GTP and remains active and bound to Raf and hence drives proliferation
What is the function of TSG’S?
Encode proteins whose function is to regulate cellular proliferation and maintain cell integrity
What is the function of proto-oncogenes?
Encode essential proteins involved in maintenance of cell growth, division and differentiation
How do you go from a proto-oncogene to an oncogene and what does this mean?
PO’s can be converted to oncogenes by a SINGLE mutation
Oncogene’s protein product does NOT respond to control influences
Oncogenes can be aberrantly expressed, over expressed or aberrantly active
What does RB1 encode?
Nuclear regulation protein
Where are mutation’s in APC commonly seen?
Colon cancer
What are the differences between Oncogenes and Tumour Suppressor genes?
Oncogene vs TSG
- Gene active in tumour VS Gene inactive in tumour
- Specific translocations/point mutations VS Deletions or mutations
- Mutations rarely hereditary VS Mutations can be inherited
- Dominant at cell level VS Recessive at cell level
- Broad tissue specificity VS Considerable tumour specificity
- Leukaemia and lymphoma VS Solid tumours
