8th Feb - Discovery of Oncogenes Flashcards
What is an oncogene?
A gene which encodes proteins whose increased activity or increased expression –> oncogenesis
Who first identified that bacteria are disease causative agents?
Koch 1876
What are Koch’s postulates?
The micro-organism must be found in abundance in all organisms suffering from the diseases, but should not be found in healthy organisms
The micro-organisms must be isolated from a diseased organism and grown in pure culture
The cultured micro-organism should cause disease when introduced into a healthy organism
The micro-organism must be reisolated from the inoculated diseased experimental host and identified as being identical to the original causative agent
Who first discovered transforming oncogenic agents in 1908?
Ellerman and Bang discovered that avian sarcoma leukosis virus could be transmitted after cell free titration to new chickens causing leukaemia
Outline Peyton Rous’ (1911) work on avian sarcoma virus
He extended Ellerman and Bang’s work by removing a chicken’s sarcoma, grinding it up and injecting the filtrate into a young healthy chicken –> sarcoma in the young chicken
Therefore there must a transmissable agent that caused tumours
How was it discovered that retroviruses are the transforming agents in Ellerman and Bangs, and Rous’ experiments?
Plaque assays
Hybridisation
Enzymatic
Outline the life cycle of a retrovirus
- Entry into the cell and loss of the envelope
- Reverse transcriptase makes DNA/RNA and then DNA/DNA double helices
- Viral DNA integrated into copy of the hosts chromosome
- Transcription
- Translation
- Assembly of many new virus particles
REPEAT
How can retroviruses develop oncogenic properties?
Oncogenic genes are likely to be incorporated into the viral genome when the viral genome is inserted into a proto-oncogene –> different protein product or viral promoter (5’LTR) leads to OE of the normal protein
This will then be replicated as part of the viral genome for new viruses
Which gene from the host cell -chromosomal DNA was incorporated into the genome of rous sarcoma virus?
c-src
How does p28 v-Sis cause cancer transformation?
p28 v-Sis is a PDGF analog thus activates the PDGFR causing transformation by autocrine stimulation
How was it discovered that p28 v-Sis acts through the PDGFR in simian sarcoma virus?
p28 v-Sis was recognized by PDGF antibodies
pDGFR expression is required for transformation by simian sarcoma virus
How does vErbB cause cancer?
It is a ‘virally hijacked’ version of EGFR, as it lacks the ectodomain of EGFR therefore has autonomous signalling
What are the two main ways of de-regulating receptor firing in cancer?
OE the receptor e.g. EGFR/ErbB1 in breast and stomach cancer
Ectodomain truncation e.g. EGFR/ErbB2 in glioblastoma, lung and breast carcinoma
What is pp60v-src?
A protein tyrosine kinase, a mutant c-src truncated so that it signals autonomously as it lacks the inhibitory tyrosine 527
What is the oncogene hypothesis?
A normal cellular gene (a proto-oncogene) can be converted to a cancer causing gene (an oncogene) by mutation
What type of mutation (i.e. dominant/recessive) convert proto-oncogenes –> oncogenes?
Dominant gain of function mutations
What are the three main processes that convert a proto-oncogene into an oncogene?
Deletion/point mutation in coding sequence
Gene amplification
Chromosome rearrangement
Who discovered DNA tumour viruses in the 1930s and how?
Shope
Applied papillomavirus to a benign tumour in a wild rabbit –> no transformation but could isolate the virus
Implanted a benign tumour from 1 wild rabbit to another domestic rabbit
Transformed tumour –> cancer w/ papilloma virus inoculation
Malignant tumour could not be further transplanted
In Shopes 1930s experiment why did the wild rabbit not get cancer and the domestic rabbit did
The wild rabbit had permissive cells which expressed all parts of the viral genome, which led to viral replication and cell lysis of infected cells with no tumour
The domestic rabbit had non-permissive cells which meant that the viral DNA was integrated into the host’s chromosomes at random sites and only part of the viral genome was expressed –> cancer
therefore viral early genes can also act as anti-oncogene interacting proteins
