Tumor suppressors as targets for anti-cancer therapies Flashcards
What are oncogenes?
Genes that promote the growth of cells or protect them from cell death
What are tumor suppressors?
Genes that halt the growth of cells or induce cell death
Are tumor suppressor genes recessive or dominant?
They are dominant
Both alleles need to be inactivated/mutated in order to get cancer phenotype
What is “loss of heterozygosity” (LOH) and what can it result from?
LOH: a way to eliminate wild-type copies of tumor suppressor genes Result from: - mitotic recombination - gene conversion - loss of the whole locus by deletion - methylation
Generally speaking, what are the two types of tumor suppressors and what are their function?
- Caretakers: DNA repair
2. Gatekeepers: cellular responses (cell death and cell cycle arrest)
What is pRb?
Enzyme regulating cell cycle passage from G1 to S phase (represses transcriptional activity of E2F)
DNA tumor viruses can inactivate it and p53 (like HPV)
What is p53, what activates it and what does it induce?
Transcriptional factor
Potent tumor suppressor activated by stress (DNA damage, oncogenes, hypoxia, telomere shortening)
Growth arrest/senescence, prevention of metastasis/angiogenesis and APOPTOSIS
What does inhibition of apoptosis and increased cell survival induce?
Cancer, autoimmune diseases, inflammatory diseases and viral infections
What does excess of apoptosis and enhanced cell death induce?
AIDS, neurodegenerative diseases, haematological diseases and tissue damage
What happens when crossing an apoptotic threshold?
Apoptosis occurs when the pro-apoptotic load of the cell exceeds its anti-apoptotic buffering capacity
What does Bax/Bak induce?
It activates caspases and induces cell death
What does Bcl-2 do?
It suppresses Bax/Bak, it is pro-survival
Describe the intrinsic pathway of apoptosis
Pro-apoptotic signals (like Bax) open a channel in the outer membrane of mitochondria and release cytochrome C which binds to Apaf-1 and procaspase 9 (in the middle of the complex), this becomes the apoptosome (the wheel of death) and induces apoptosis
Describe the extrinsic pathway of apoptosis
Death receptors are activated and activate the DISC complex which induces a caspase cascade starting with caspase 8 leading to apoptosis
What does p53-mediated apoptosis involve?
p53-mediated apoptosis involves both extrinsic and intrinsic pathways
What are p53 -/- mice prone to?
They are prone to tumors (decreased life expectancy)
What does Mdm2 do and what happens if it is amplified?
In healthy cells Mdm2 suppresses p53
If amplified, it suppresses it too much and p53 losses control on tumor growth
How is p53 restoration possible for tumor regression?
Most cancers eliminate p53 function, but it seems that its pathway remains intact so resurrecting it might provide a cancer therapy
What are the 2 strategies to reactivate p53?
- Mutant p53: 50% of tumors express mutant p53
Solution => small molecules which stabilize the folding of mutant p53 - Wild type p53: in 50% of tumors WT-p53 is rendered non-functional by deregulated p53 inhibitors
Solution => small molecules which release p53 from its inhibitor (Mdm2)
What can be said on p53 mutations?
- Occur in 50% of human tumors
- The majority of p53 mutations are point missence
mutations - Cluster in the core domain (unable to bind to DNA)
- Result in PARTIAL unfolding of the core domain
- Mutant p53 proteins are over-expressed in tumors
What is PRIMA-1, what does it do and how does it do it?
PRIMA-1 = p53 reactivation and induction of massive apoptosis:
- restores the DNA binding
- rescues p53 conformation and transcriptional transactivation function of p53
- induces apoptosis in tumor cells in a mutant p53-dependent manner
What is the dual mechanism of action of APR-246 (structural analog of PRIMA-1)?
- Induces oxidative stress leading to cell death
2. Restores mutant p53 conformation and transcriptional transactivation function (back to WT-p53) leading to cell death
