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?
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 tyrosine kinase receptor that does not switch off and thus drives uncontrolled proliferation–CML
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
these are signal transduction proteins
What is an example of an inherited cancer?
Retinoblastoma – malignant cancer of the developing retinal cells
What mutation causes retinoblastoma?
RB1 TSG gene on Chr 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
p16-INK4- cell cycle regulator (CDK-I)
MLH1- mismatch repair
In what form is p53 inactive?
When it is bound to MDM2, dissociates when cell is under stress
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)
mutation of a single gene is enough to make it cause cancer despite being a TSG
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 this mutation (APC) developing colon cancer?
90%
What signalling pathway is APC involved in?
WNT signalling- helps control beta-catenin
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–> Polyps
- K-ras mutation (+DNA hypomethylation )will make the polyps –> adenomas
- P53 mutation will result in adenoma–> carcinoma
- carcinoma–> metastasis
what are the 4 ways oncogenes can be activated
- mutation in coding sequence
- gene amplification
- chromosomal translocations
- insertional mutagenesis (eg viral infections)
how does a defect/ mutation in Ras cause cancer
when bound to GTP, Ras becomes active–> binds Raf–>activates ERK–>proliferation
therefore dephosphorylation of GTP–>GDP deactivates Ras –> unbinds from Raf and prevents ERK cascade activation
mutated Ras fails to dephosphorylate GTP and hence stays bound to Raf and keeps activating ERK and driving phosphorylation
what do TSG’s usually encode
TSGs encode proteins whose function is to regulate cellular proliferation and maintain cell integrity
what do (proto)oncogenes usually encode
Proto-oncogenes code for essential prot
eins involved in maintenance of cell growth, division and differentiation
