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
