Lecture 9 - Tumor Suppressor Genes Continued... Flashcards
How do tumor suppressor genes generally function? List five mechanisms in which this inhibition can function.
Tumor suppressor genes generally function to inhibit cell proliferation and survival
Mechanisms: 1 - p53 2 - rb 3 - NF1 4 - APC 5 - pVHL
Essentially, they also inhibit proliferation during differentiation. This means the loss of tumor suppressor genes is REALLY REALLY bad
What are Neurofibromas? What is their main feature(s)?
Neurofibromas are a familial cancer syndrome whose main features include benign tumors in cell sheets surrounding the PNS (Peripheral Nervous System).
They are strongly influenced by a genetic background (familial).
Tumors can contain cells from a range of cell types. Benign tumors can quickly switch to malignant following further mutations.
What is NF1 and what is its importance in neurofibromas?
How might NF1 explain the multiple tumor cell lines?
NF1, or Neurofibromin, is a GAP protein responsible for GTP hydrolysis and the inactivation of the activated Ras.
When functioning normally, Ras being inactivated, growth factor signalling levels temporarily decrease until needed again.
Mutation of NF1 causes Ras to be over-active/constitutively turned “on” leading to increased growth factor signalling and proliferation.
The complexity of multiple tumor cell lines may be a result of co-proliferation in other cells possibly due to haploinsufficiency (one bad copy of NF1). Losing just a single copy of NF1 is bad enough already as it is already wayyy more likely for tumorigenesis to occur.
Explain the Schwann/Mast cell experiment with NF1 cells.
Nf1 -/- plus Nf1 +/+ = normal carrier, few tumors/cancer
Nf1 -/- plus Nf1 +/- = partial loss, many tumors and cancer
What is FAP? How is the beta-catenin pathway altered here? What are the direct effects of this?
FAP, or Familial Adenomatous Polyposis, is present in digestive/colon cancers. Mostly, the developed polyps are benign… but can become malignant.
In FAP patients, the APC component of the in-cell beta-catenin complex is defective. This leads to beta-catenin leaving the complex shell to bind with Tcf/Lef on the genome. In essence, it prevents beta-catenin from binding properly to the initial complex.
This promotes proliferation and inhibits differentiation.
In FAP, why is is ok if some cells go bad? [in relation to cell life-span]
Since the half-life of cells in the colon lumen is 1-2 days, it’s ok if some cells go bad as they are quickly replaced. There has to be a period of persistent mutation in order to start a problem.
What can the loss of APC also lead to? Name two.
1 - abnormal cell motility
2- Chromosomal instability
What is VHL?
Describe the cycle under both normoxia and hypoxia conditions. What is the futile cycle?
What are some of the more notable HIF-1alpha/beta targets?
VHL, or Von Hippel-Lindau Diseas, is a hereditary predisposition to a variety of tumors. This includes carcinomas of the kidney, blood vessels, and CNS (cenral nervous system).
Under normal oxygen conditions (normoxia), the HIF-1alpha (bean-like) protein is produced and immediately destroyed following binding to pVHL, dephosphorylation, and polyubiquitylation. Degradation occurs in proteasome snare. This is known as the futile cycle since the HIF-1alpha is degraded right away.
Under abnormally low oxygen conditions (hypoxia), the HIF-1alpha binds to HIF-1beta on the genome, leading to the transcription of genes.
Some notable HIF-1alpha/beta targets of transcription include VEGF, PDGF, TGF-alpha. HIF-1alpha/beta also increases P13K activity and its pathway via Ras.
Describe the ubiquitylation process. What are proteasomes important?
Target protein first undergoes polyubiquitylation by binding with ATP and Ubiquitin-Ligase complexes (Ubi)
*Ubi are each made up of E1+E2+E3
After this, the protein enters the proteasome at the top while the Ubi tail trails behind and is capped at the top opening.
The proteasome snare then breaks apart the Ubi chain by dephosphorylation of ATP into ADP. Protein is also broken down into amino acids.
Over 80% of mammalian proteins are degraded in proteasomes.
What are some of the advantages of Ubiquitin-regulated proteolysis? Give five.
1 - Unidirectional 2 - Rapid 3 - Sensitive 4 - Localized 5 - Specific
