Oncogenes and Tumour Suppressors Flashcards
What are the major functional changes in cancer?
- Increased growth (loss of growth regulation, stimulation of environment
promoting growth e.g. angiogenesis) - Failure to undergo programmed cell death ( apoptosis) or senescence
- Loss of differentiation (including alterations in cell migration and adhesion)
- Failure to repair DNA damage (including chromosomal instability)
What are the four classes of cancer genes
- Oncogenes
- Tumour suppressor genes
- Apoptosis genes
- DNA repair genes
Describe regulated cell growth
Normal cells are signalled to increase in number with an accelerator signal
Once the cell number has been reached the cells stop proliferating with a brake signal
describe deregulated cell growth
Cancer cell receives an increased accelerator signal to proliferate quickly
There is an issue with the brake signal and cell division isn’t suppressed
Which hallmarks of cancers relates to oncogenes
- sustaining proliferative signal
- Enabling replicative immortality
- Genome instability and mutation
Which hallmarks of cancer relate to Tumour suppressor genes
- Evading growth suppressors
- Genome instability and mutation
- Resisting cell death
How do oncogenes lead to cancer
Their normal job is to make cells divide, driving cell division forward
In cancer, pick up mutations that mean they are permanently active
Oncogene: “Gain of function”
How to tumour suppressor genes lead to cancer
Even if you have a mutation in an oncogene that pushes cell division forward, if your tumour suppressor genes are strong enough, they should still be able to counteract the oncogene
In cancer, pick up mutations that switch the gene off.
Tumour Suppressor gene: “Loss of function”
Define proto-oncogene
A “normal” gene that has the potential to become an oncogene when mutated
Describe how oncogenes were discovered
Studies of retroviruses essential in understanding oncogenes
Landmark experiments:
- Frances Peyton Rous began his work in 1910 that lead to the discovery of Rous sarcoma virus (RSV).
- 50 years later he received the Nobel Prize in Medicine in 1986
- In 1911 when a farmer brought Rous a prized Plymouth Rock hen that had a large tumour growing in the chest muscle,
He used the cell free filtrate from the chicken sarcoma and was able to induce sarcomas in healthy chickens
Describe the Rous’ protocol
- Tumours developed weeks later
- Taking the new sarcoma, filtrates produced could also induce tumours in other chickens
- The cycles could be repeated indefinitely. Also 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
- Discovery that this sarcoma was transmissible through viruses- Rous Sarcoma Virus
How can viruses transmit the src Oncogene
- RSV retrovirus integrates into the genome - oncogenic virus
- Fibroblast which was infected with RSV proliferate abnormally and transforms into cancer cells
- RSV stole genes from chicken cells and incorporated it into their genome, cellular origin
SRC genes exist in human cells (c-src/ v-src)
Why are proto-oncogenes in our cells
They are involved in normal proliferation
Test for possible oncogenes:
- bits of DNA transfected into mouse fibroblasts.
- used immortalized mouse cells (not transformed / not tumorigenic)
- occasionally a piece of DNA caused cell transformation and cells were also tumorigenic.
- then have to isolate the human gene that had caused the transformation of the mouse cells
- discovery of ras oncogene
Describe the capture of c-src by retroviruses
- During evolution, the virus can acquire fragments of genes from the host at integration sites and this process results in the creation of oncogenes
- The oncogene product was characterised as a 60kDa intracellular tyrosine kinase
- Can phosphorylate cellular proteins and effect growth
How can DNA viruses lead to cancer
DNA viruses can cause lytic infection leading to the death of the cellular host or can replicate their DNA along with that of the host and promote neoplastic transformation
Encode various proteins along with environmental factors can initiate and maintain tumours
How can RNA viruses lead to cancer
Integrate DNA copies of their genomes into the genome of the host cell and as these contain transforming oncogenes they induce cancerous transformation of the host
What is the oncogene hypothesis
Normal genes are switched to oncogenes via carcinogens such as:
- Chemicals
- physical
- Viruses
what are the 4 proteins involved in NORMAL transduction of growth signals
- Growth factors
- Growth factor receptors
- Intracellular signal transducers
- Nuclear transcription factors
What are the mutations that turn proto-oncogenes into oncogenes
- Deletion
- Duplication - too much proteins made
- Inversion
- Translocation
- Subtle mutations - point mutations
GAIN OF FUNCTION MUTUATIONS
Describe the formation of the Philadelphia chromosome - Translocation
- Chromosomal translocation between chromosomes 9 and 22
- genes coding for BCR and ABL are brought closer together
- Creates a fusion protein: BCR-ABL
- As a result of this translocation the tyrosine kinase activity of the oncogene ABL is
constitutive leading to abnormal proliferation - Seen in 95% of Chronic Myelogenous Leukaemia (CML) cases
Describe HER2 mutation in oncogene formation - Gene Amplification
- Coded by the ERBB2 gene – amplified in cancer
- Human epidermal growth factor receptor 2
- Growth factor signalling
- Important in subsets of breast cancer
- There are now drugs that target HER2 – eg Trastuzumab (Herceptin)
Describe Ras mutation in oncogene formation - Point Mutations
G- T change - Glycine to Valine
Ras signaling pathway:
- Ras GTP to GDP cycling
- Ras – GTP binding protein.
- GTP – active
- GDP – inactive
Mutated Ras - GTP hydrolysis is Inhibited. Protein stuck in active state - CONSTITUTIVELY ACTIVE
Describe the MYC Oncogene family
- Consists of 3 members: C-MYC, MYCN and MYCL which encodes c-myc, n-myc and l-myc
- Originally identified in avian myelocytomatosis virus (AMV)
- It is over-expressed in majority of human cancers and contributes to the cause of at least 40% of tumours
- Encodes a helix-loop-helix leucine zipper transcription factor that dimerises with its partner protein, Max, to transactivate gene expression
- Sub activation is a result of chromosomal translocation
How were tumour suppressor genes identified and discovered
- in 1969 Henry Harris performed somatic cell hybridisation
- Fusion of normal cells with tumour cells made cells with chromosomes from both parents that weren’t capable of forming tumours.
- Genes derived from normal parents acceded to suppress tumour development.
The first tumour suppressor gene was identifies by studies of retinoblastoma
