lecture 9 - tumor suppressor

Question 1

1) Describe the different levels of expressivity of Neurofibromas, as well, what is the normal function of the NF1 gene? What is this protein classified as and what are the consequences of NF1 -/-? How may someone get Neurofibromatosis?

Answer 1

• described as café au lait spots or large benign tumor like growths.
• The normal function of the NF1 gene is to shut off Ras, by taking away a phosphate group and turning it into its inactive GDP phase.
• classified as a GAP protein
• if NF1 is missing, Ras is never turned off and the rate of proliferation, etc is high
• This may be a familial cancer syndrome or even occur sporatically

Question 2

2) Is NF1 +/- good enough to have normal phenotype?

Answer 2

• No, NF1 is not haplosufficient. Less NF1 protein present to turn off Ras, rates of proliferation are still very high.

Question 3

3) Why do cancer cells recruit mast cells (neurofibromas)

Answer 3

why.

Question 4

4) Describe at the molecular level the consequences of APC -/- and what type of cancerous growth is associated with that.

Answer 4

• APC controls Beta-catenin in the Wnt signaling pathway. Loss of APC leads to hyperactive Beta-catenin thus increasing cell proliferation and reducing differentiation.
• usually found in Familial Adenomatous Polyposis (FAP)

Question 5

5) Describe the cycle of APC and Beta-Catenin in Colonic Crypts in both normal cells and with FAP patients.

Answer 5

Normal cells:
- The bottom of the crypt contains many stromal cells the send intense signals through the Wnt signaling system, causing Beta-catenin to be on, which increases the proliferation of the stem cells, as the cells migrate up the crypt, APC is turned on and Beta-catenin is turned off, this slows proliferation and allows differentiation and specialization of cells. These cells undergo apoptosis after a few days and new ones are made
Cancerous cells:
- Same thing at the beginning, but there is a mutation with APC, most likely I cannot bind to beta-catenin to shut it off, it may also be truncated, etc. Proliferation continues up the crypt, cells don’t differentiate and form large tumor like polyps, these don’t’ undergo apoptosis.

Question 6

6) Give one other thing that may lead to a loss of APC

Answer 6

• abnormal cell motility, non disjunction may occur

Question 7

7) What is VHL? What type of cancers arise from this disease? What is pVHL and what is its main function?

Answer 7

Von Hippel Lindau disease, associated in carcinomas of the kidney, blood vessels, CNS, etc.
Main function of pVHL is to shut down HIF-1

Question 8

8) How does pVHL turn off HIF-1, what condition is that called? In what condition is pVHL unable to turn off HIF-1? What are the consequences of this?

Answer 8

• It targets HIF-1 for destruction via ubiquitylation, which causes HIF-1 to be destroyed by a proteasome. Only occurs when oxygen is present, called normoxia.
  During hypoxia, in the lack of oxygen, HIF-1 is not destroyed. Since HIF-1 targets many growth factor genes, this promotes angiogenesis, etc. It targets genes such as PDGF, TGF and even increases activity of PI3K.

Question 9

9) Describe at the molecular level why oxygen is needed to target HIF-1 and allow binding of pVHL to it.

Answer 9

• Oxygen is required so the enzyme proline hydroxylase may oxidize HIF-1, if oxygen not present, this won’t occur and HIF-1 escapes destruction.