Lecture 5: Cancer 2 Flashcards
What are retroviruses?
Very small (70-100nm) viruses with a single stranded RNA genome
When and how were retroviruses discovered?
In 1911 when Peyton Rous (who got the Nobel Prize) discovered that you can infect a healthy bird with a cell free extract (which contains the retrovirus) from a tumour in an infected bird.
How can one virus cause both benign and malignant tumours?
Oncogenes facilitate the development of malignant tumours.
Describe the genome of the Rat Sarcoma virus and what each gene does.
There are LTR regions (long terminal repeats) on each end of the genome.
The GAG gene encodes for the protein shell which surround the retrovirus genome and protects it from environmental RNAases.
The ENV gene encodes for the envelope/surface proteins, which are receptors which give the virus its specificity.
The POL gene encodes the reverse transcriptase, which can make double stranded DNA from single stranded RNA. This enables the retrovirus to infect DNA-containing organisms, e.g. humans, rats, etc.
In the malignant strain, there is an extra gene, Ras, which is an oncogene.
Discuss the differences between c-Ras and v-Ras.
c-Ras is cellular Ras and v-Ras is viral Ras. v-Ras has a valine where c-Ras has a glycine.
c-Ras can be swtiched on by GEF and off by GAP and undergoes the normal function in the cell. However, v-Ras cannot be turned off and is an oncogene, so causes cancer.
Activated Ras has downstream effects including a protein kinase cascage, which causes proliferation. If too much Ras is activated, too much uncontrolled proliferation occurs, which causes cancer.
Why do retroviral oncogenes exist?
These oncogenes enforce S phase entry on infected cells to enable retrovirus replication. The cells cannot stop division once in S phase. There is uncontrolled proliferation. The virus needs the host cells to express genes to replicate itself (the virus).
Oncogenes subvert normal pathways in order to reproduce. The cellular equivalents to the oncogenes can usually be stopped/switched off (controlled) and have normal, essential functions. Oncogenes are dominant over their cellular equivalents.
Why is Ras such a common cellular oncogene?
It is commonly mutated in human cancers (about 20% of all tumours).
- There is only one single mutation required to make the normal version an oncogene. A glycine must be replaced with a valine.
- The oncogene version is dominant over the normal version, so the normal ras on the other chromosome cannot help.
What are DNA tumour viruses?
Small viruses which have more genes that retroviruses. An example is the Human Papilloma Virus (HPV), which cause Cervical carcinoma (cancer). You can be vaccinated against them. Deletion analysis (taking out one gene at a time and seeing if the virus mutant still causes a tumour) indicates that only the E6 and E7 proteins are required for transformation. These two genes are not similar to any genes in our genome.
How do E6 and E7 cause cancer in humans?
Normally the retinoblastoma protein (Rb) binds to and inhibits E2F (a transcription factor which initiates S phase). However, E7 binds to Rb better than E2F does. This means that E2F is freed and continually committing the cell to S phase, causing uncontrolled proliferation. Inactive Rb stimulates gene expression for the initiation of S phase.
Normally p53, another transcription factor, transcribes genes that cause apoptosis and cell cycle arrest. As these are unfavourable for the virus, the virus inhibits p53. E6 binds to and inhibits p53.
What is p53 and what does it do?
A transcription factor which is incredibly important in the prevention of cancer and also a tumour suppressor gene. It acts as a gene regulatory protein and causes the transcription of genes which cause apoptosis or cell cycle arrest. Depending on the severity of the damage, p53 may either drive the damaged or abnormally proliferating cell to commit suicide by apoptosis or may trigger a mechanism that bars the cell from dividing so long as the damage remains unrepaired.
One way p53 causes cell cycle arrest is by binding to DNA to cause transcription of p21. This gene encodes a protein, p21Cip1, which binds to and inhibits the cdk complexes required for the cell cycle to progress.
p53 can cause apoptosis by transcribing pro-apoptotic proteins, such as Bax. Bax inhibits Bcl-2, which is anti-apoptotic and usually prevents the leakage of cytochrome c from the mitochondria (causes Apaf-1 and caspase accumulation, then a caspase cascade and apoptosis).
When telomeres get too short, p53 is activated and inhibits further cell division.
Give two examples of tumour suppressor genes?
p53 and Rb (retinoblastoma protein).
What are tumour suppressor genes?
Genes which stop uncontrolled proliferation/tumourogenesis or kill cells and by doing so, prevent cancer.
They are very commonly mutated in human cancer (loss of function mutations).
Mutations to tumour suppressor genes are recessive, so both alleles of the gene must be mutated for the function to be lost.
How are E6, E7, p53 and Rb related?
E6 and E7 are proteins released by a virus to cause uncontrolled proliferation (cancer) in a host cell.
E6 binds to and inhibits p53.
E7 binds to and inhibits Rb.
Which two types of mutation cause cancer?
- Overactivity mutation: oncogene stimulates cell proliferation
- Underactivity mutation: inactivates tumour suppressor genes (needs to have a mutation in each allele)
How can an individual be predisposed to cancer due to underactivity mutations?
An individual may inherit one already-mutated allele of a tumour suppressor gene from parents, which means they are predisposed to cancer, because one random mutation event (to the other allele), would knock out the tumour suppressor gene. That individual is therefore likely to develop cancer earlier in life (one random mutation takes less time than two).
