Oncogenes and Tumour Suppressor Genes Flashcards
Define what a hallmark of cancer is
Characteristic that normal cells have to require to become tumour cells
Major functional changes in cancer
Increased growth (regulation, environment )
Failure to undergo apoptosis
Loss of differentiation
Failure to repair DNA damage
Oncogenes function
Components of GF signalling pathways = reg. cell proliferation + survival in response to GF stim
↳ mutated = ↑ product or altered products have ↑ activity = act in a dominant manner
Tumour suppressor gene function
Stop signal to uncontrolled growth, may inhibit cell cycle or trigger apoptosis
Describe the effect of gain of function in oncogenes
an altered gene whose product can act
in a dominant fashion to help make a cell cancerous.
= leads to stimulated cell proliferation
Describe how there is a loss of function in TSG and their its effect
2 inactivating mutations for TS functionally eliminate TSG = stim cell proliferation
=
a normal process to maintain control of cell division is lost
= enhances the likelihood that a cell can become cancerous
Explain how tumour development in chickens led to the discovery of Rous Sarcoma Virus
The carcinogenic agent was small enough to pass through a filter
Although the filter used excluded bacteria it was not small enough to exclude viruses
Rous concluded that a virus must be responsible for the induction of tumour formation
How to induce sarcomas in other chickens
Chicken w/sarcoma in breast muscle
Remove sarcoma and break up into small chunks of tissue
Grind up sarcoma with sand
Collect filtrate that has passed through fine pore filter
Inject filtrate into young chicken
Observe sarcoma in injected chicken
List the reaasons why retroviruses were important experimentally
Technological advances
Funding
Improved tissue culture techniques
The discovery of reverse transcriptase, RNA genome, replicates via DNA intermediate and that they are enveloped
Describe + explain discovery of the fundamental principle of oncogenes
Oncogenic transformation by RSV was found to be caused by an extra gene contained in its genome = ‘oncogene’ v-src
Homologous sequences were found in uninfected chickens and other OG
Fundamental principle: Oncogenes are alerted forms of normal genes or proto-oncogenes
Describe oncogene hypothesis
V-src homologous seq in uninfected
So some genes of cancer causing viruses were mutated forms of the cellular gene not viral genes
Conclusion = rous sarcoma viral gene was in fact a host gene that had been ‘kidnapped’ by the virus (and ‘transformed’ into an oncogene)
Describe capture of c-src by retrovirus
c-src (in host cell chromosomal DNA) included into viral sequences with the dsDNA provirus (from infection then reverse transcription)
Which is accidentally integrated next to c-src
Then packaged into capsid leading to RSV virion carrying src sequences
Describe and explain the effect of integration of gene fragments in viruses
During evolution, virus can acquire gene fragments from host at integration sites = creation of oncogenes
Can phosphorylate cellular proteins and effect growth
Explained how Bishop/varmus showed that an oncogene was responsible for causing cancer
Identified v-src oncogene for causing cancer
Hybridization experiments = c-src gene was present in genome of many species
Showed that host cell c-src gene was normally involved in +ve regulation of cell growth and cell division
Following infection - v-src oncogene was expressed at high levels in host cell = uncontrolled cell division/growth and cancer
Explain how cells can be transformed
Various agents, including radiation, chemical carcinogens,
and
Exogenously added viruses, may transform cells by “switching on” the endogenous oncogenic information
What do DNA viruses:
Encode
What can they cause
Encode various proteins along with environmental factors can initiate and maintain tumours
Can cause lytic infection = death of cellular host or can replicate own/hosts’ DNA and promote neoplastic transformation
What do RNA viruses do
Integrate DNA copies of their genomes into HC genome and as these contain transforming oncogenes they induce cancerous transformation of the host
Viral oncogenes transmission - how
Viral oncogenes can be transmitted by either DNA or RNA viruses
Describe what can lead to the activation of oncogenes
OG captured by animal retroviruses
+
altered in human cancer, activated by mutations, insertions, amplifications and translocations
Describe oncogene activation
Translocation = DNA regulatory seq translocated from distant site alters expression of downstream gene
Mutation/deletion = protein w/altered structure/function
Duplication = ↑ synth. of encoded protein - activates by insertion nearby P-OG
- ↑ synth. of encoded protein
OR - Synthesis of a protein containing portions encoded by different genes. The fusion protein is no longer under normal control
Thus a protein-coding gene translocated from distant site fuses w/portion of gene causing formation of a fusion gene
4 types of proteins are involved in the transduction of growth signals
Growth factors
Growth factor receptors
Intracellular signal transducers
Nuclear transcription factors
Explain the involvement of oncogenes with ras
Oncogenes act as GF, GFR and intracellular signalling molecules
Ras and Raf activate the ERK MAP kinase pathway,
leading to the induction of additional genes (e.g. fos) that encode potentially oncogenic transcriptional regulatory proteins
Ras proteins - definition
RAS proteins are small GTPases that are normally bound to GDP in a neutral state
Ras mutations - effect
Loss of GTPase activity of the RAS protein
Hyperactive ras due to mutation so DNA damage repair is not allowed to happen
