Edmead exam prep Flashcards
What is the role of Advexin in cancer therapy?
Adenoviral delivery of the wild type p53 to tumour cells.
What is the rationale behind the use of Advexin in cancer therapy?
> 50% of human cancers have a mutation in p53 - DNA binding region which inhibits its ability to act as a transcription factor.
p53 works as a tetramer so even if only one allele is mutated there is a good chance of incorporating mutated p53 into the tetramer resulting in a non-functional structure.
What impact does the structure of p53 have on its resiliance to mutation?
IT is a tetramer.
If only one allele is mutated there is still a good chance of a non-functional structure resulting as we still need all 4 sub-portions to work.
What is the normal role of p53?
TSgene. Detects damaged DNA and causes cell cycle arrest by upregulating CDKIs such as p16.
If the DNA is too damaged then p53 will induce apoptosis by upregulating Bad/Bax.
How does p53 normally cause cell cycle arrest when detecting damaged DNA?
In upregulates CDKIs such as p16.
How does p53 induce apoptosis if DNA is too damaged?
Upregulates Bad/Bax.
Advexin is a treatment which involves what?
Introduction of wildtype p53 to tumour cells in head anc neck cancer but there are limitations to do with the specific targeting.
Why is cancer so difficult to treat?
- The cells look like the self, does not trigger the immune system.
- Often well established and spread before detected (link to newer ways of detecting it).
- Polygenic in nature, many mutated proteins may be involved - hence many things will need to be targeted to control growth and induce apoptosis.
- Most anti-cancer therapies are not specific and kill all rapidly dividing cells and causes side effects: damage to bone marrow, gut, hair loss, sterility.
- Cancer is invasive: hard to establish a boundary for surgical removal.
- Resistance can occur to drugs through mutations to binding sites, selection pressures, overexpression of drug efflux pumps.
- Hypoxic middle area of tumours: chemo needs dividing cells, radio needs oxygen.
- Resurgence of cancer if not all cells are destroyed.
Leukaemias are associated with the expression of fusion proteins, what are they?
Many leukemias begin when a large piece of one chromosome becomes loose and reattaches to another chromosome. This can bring together two unrelated genes that can wreak havoc on the cell.
New studies suggest that some of these fused genes produce proteins that deliver a double whammy. They shut down genes that help repair mistakes in DNA, and they activate genes that help the cells proliferate. The result is uncontrolled growth of cells with lots of genetic mistakes.
What are two examples of fusion proteins?
AML1/ETO
PML/RAR
AML fusion proteins induce genes involved in the maintenance of the stem cell phenotype and repress DNA repair genes, mainly of the base excision repair pathway.
What will be the likely result of this?
Cancer.
Outline the role of bcl-2 in normal cells and cancer cells.
It inhibits Bax to prevent the formation of membrane pores.
In cancer it is often translocated to a region of high expression for example, in B cell lymphoma next to the Ig enhancer. This tilts the cell in favour of survival despite any DNA damage etc.
Bcl-2 is often translocated next to __ enhance in ______ lymphoma.
In cancer it is often translocated to a region of high expression for example, in B cell lymphoma next to the Ig enhancer. This tilts the cell in favour of survival despite any DNA damage etc.
Bcl-2 is pro-survival. How?
BCL-2 is localized to the outer membrane of mitochondria, where it plays an important role in promoting cellular survival and inhibiting the actions of pro-apoptotic proteins. The pro-apoptotic proteins in the BCL-2 family, including Bax and Bak, normally act on the mitochondrial membrane to promote permeabilization and release of cytochrome C and ROS, that are important signals in the apoptosis cascade. These pro-apoptotic proteins are in turn activated by BH3-only proteins, and are inhibited by the function of BCL-2 and its relative BCL-Xl
Why is Bcl-2 not considered a proto-oncogene?
Bcl-2 is specifically considered an important anti-apoptotic protein but it is NOT considered a proto-oncogene because it is not a growth signal transducer.
