Oncogenes and Tumour Suppressor Genes Flashcards
List some hallmarks of cancer
- Evasion of apoptosis
- Angiogenesis
- Invasion of tissues
- Disregard of signals to stop proliferating
- Disregard of signals to differentiate
- Capacity for sustained proliferation
Describe the cell cycle briefly
- G0 - quiescent phase (not replicating)
- Cells stimulated to enter the cell cycle
- G1 - duplication or growth of contents of the cell not including the nuclear material and growth in cell mass and size
- There is a G1 checkpoint to check that the cell is the right size and there are the favourable conditions to continue e.g. growth factor etc
- S phase - chromosomal duplication
- G2 phase - cell continues to grow and prepare for mitosis
- G2 checkpoint - checks for errors in DNA and mutation / duplication prior to mitosis
- Mitosis
- Back into interphase / G0
What is the significance of cyclin within the cell cycle and what other proteins are involved in the cell cycle?
- Permanent activation of cyclin can drive cells through checkpoints in the cell cycle
- There is destruction of certain proteins such as cyclin, CDK, CDK inhibitors etc
1) What is a proto-oncogene?
2) What is an oncogene?
1)
- Genes that code for maintenance of cell growth, division and differentiation
2)
- An aberrant form of a proto-oncogene resulting in proteins that no longer respond to control influences and cause cancer development
Give 4 mechanisms by which oncogenes can arise from proto-oncogenes - i.e. activation of oncogenes. Give an example in 2 of these
- Mutation in the coding sequence - either point mutation or deletion
- Gene amplification - multiple gene copies of the proto-oncogene so they can now be thought of as oncogenes as their is overexpression of the protein that promotes cell growth and division
- Chromosomal translocation (chimaeric genes) - especially a problem if one of the pieces of translocated DNA is a promoter, thereby enhancing expression of the other gene, causing uncontrolled proliferation e.g. in Burkitt’s Lymphoma
- Chromosomal translocation (insertional mutagenesis) - fusion gene producing abberant protein e.g. Philadelphia Translocation
Describe the role of Philadelphia Translocation in the pathophysiology of some cancers - what is it and what happens?
- Philadelphia chromosome formed from the philadelphia translocation as a result of translocation of sections of DNA from chromosome 9 and 22
- Forms a BCR-ABL fusion gene which is an oncogene causing cancer
What more complex signalling cascade pathway is the Ras pathway part of?
- The MAPK signalling pathway (mitogen activated protein kinase cascade)
Describe the physiological actions of Ras, and thus how aberrant mutant Ras can cause cancer
- Ras binds to GTP and upon binding, is activated
- Note Ras also can dephosphorylate GTP to GDP as an autoregulatory mechanism
- Ras now interacts with RAF
- RAF signals by phosphorylation and activates the kinase signalling cascade to promote cellular proliferation
- Oncogenes for Ras cause aberrant Ras production, there is little dephosphorylation of GTP to GDP so there is plenty of GTP available for Ras to bind to and for it to become activated
- Lots of Ras activated and can bind RAF which promotes cellular proliferation via the kinase signalling cascade. Due to the XS Ras and therefore XS RAF mediated action, there is overproliferation of the cells - cancer
Which mutations result in impaired GTP hydrolysis for the Ras oncogene?
- Mutations at codons 12 (Gly), 59 (Ala) and 61 (Gly)
Describe the tissue specificity of Ras mutations in oncogenesis and what is it?
- Tissue specificity - different (aberrant) isoforms of the enzyme can result in oncogenesis unique to different tissues
- E.g. K-ras in lung, colon and pancreatic cancer while…
- N-ras in acute myeloblastic leukaemia
What do tumour suppressor genes do physiologically - don’t have to detail the different functional categories, just what is their basic function?
- The regulate cell growth and proliferation - the ‘brakes’
- They also maintain cellular and genetic integrity
1) Describe the priniciples of Knudson’s 2 hit hypothesis, sporadic and familial mutation
2) This is relevant in oncogenesis in regards tumour suppression genes or oncogenes - and give one exception?
1)
- In order for oncogenesis to occur, usually in TSGs, you must have mutation in both alleles for a gene
- These mutations can be familial (germline mutation) which are inherited
- Or sporadic (somatic mutations)
- In familial mutation, you inherit one mutated TSG, but do not have cancer yet because the other wild-type gene is still functioning, however if this is also mutated after one sporadic mutation picked up in your lifetime and loss of heterozygosity (i.e. both are now mutated TSGs so LOH as both are now the same), then you develop cancer
- In sporadic mutations, you must pck up 2 sporadic muations in your lifetime which is unlikely, in order to develop cancer
2)
- Relevant for TSG cancers
- Exception = p53 cancers
How may the presentation of cancer in people who have had a familial mutation differ from those who require 2 sporadic mutations?
- Earlier onset
- Bilateral tumours in paired organs
- Synchronous or successive tumours
- Tumours in different organs in the same individual
Describe the pathophysiology of Retinoblastoma and then discuss briefly how its presentation may differ in those who inherited a germline mutation (familial mutation) and those who had purely sporadic mutations causing the cancer
- Malignant cancer of developing retinal cells
- Mutated RB1 tumour suppressor gene on the chromosome 13q14
- RB1 encodes a protein that is involved in regulation of the cell cycle, so an aberrant RB1 will result in an abnormal cell cycle, causing cancer
- Sporadic disease is usually unilateral whereas familial may also be bilateral or multifocal
Describe what activates p53, its physiological actions and how it autoregulates
- p53 is activated in response to DNA damage / cellular stress
- p53 has the following 4 effects:
- DNA repair
- Arrests growth at G1 - p21 (Waf1) - binds and inhibits cyclins and cyclin dependent kinases to arrest growth
- Promotes apoptosis - via Bax - a member of the Bcl-2 family. If p53 fails to repair the cell, it commits the cell to apoptosis
- Promotes transcription - of p21 and Bax and Mdm
- Inhibits growth by stimulating Mdm2 synthesis, Mdm2 causes degradation of p53 - this is a negative feedback mechanism
