Tumor Suppressor Genes (Herschman)

Question 1

Tumor Suppressor Genes

What are the chromosomal characteristics of Burkitt’s Lymphoma?

Answer 1

A translocation between Chromosome 8 and either Chromosome 14, 22 or 2

Question 2

Tumor Suppressor Genes

Describe the “fusion gene” found in patients with Burkitt’s lymphoma

Answer 2

An IG (immunoglobulin) promoter from chr14, 22 or 2 combines with the c-myc gene (a transcription factor) from chr8 such that c-myc is very actively expressed

Question 3

Tumor Suppressor Genes

How can a chromosomal translocation cause cyclin D1 to be overexpressed?

Answer 3

PRAD1/Cyclin D1 gene translocates with IgG promoter. Overproduction of cyclin D1 results in overphosphorylation of RB so G1 to S phase transition genes are constitutively on.

Question 4

Tumor Suppressor Genes

What is the Philadelphia chromosome?

Answer 4

Chr22:9 translocation found in patients with Chronic Myelogenous Leukemia

Question 5

Tumor Suppressor Genes

What is the fusion protein found in patients in CML and what does it do?

Answer 5

The translocation causes ABL (a tyrosine kinase) to fuse with BCR forming BCR-ABL fusion protein. This new protein has very high kinase activity.

Question 6

Tumor Suppressor Genes

Name the 3 ways dominant oncogenes are activated in human tumors

Answer 6

1. Point Mutations - e.g. ras, G(alpha), RAF
2. Chromosomal translocations - e.g. myc, abl, PRAD1
3. Amplification of oncogene - e.g. HER2, EGFR

Question 7

Tumor Suppressor Genes

Why is the RB protein considered a tumor suppressor gene?

Answer 7

RB binding prevents E2F from transcribing genes needed to transition from G1 to S. If there is no functional RB, cancer can result.

Question 8

Tumor Suppressor Genes

What does p53 do?

Answer 8

DNA repair. p53 levels elevate in response to DNA damage. This induces expression of cyclin dependent kinase inhibitors.

SPECIFICALLY-It can (1)activate DNA repair proteins when DNA has sustained damage.

 (2) It can induce growth arrest by holding the cell cycle at the G1/S regulation point on DNA damage recognition (time for DNA to be fixed)   (3) It can initiate apoptosis, if DNA damage proves to be irreparable.

Question 9

Tumor Suppressor Genes

What is GAP and how does it act as a tumor suppressor?

Answer 9

GAP hydrolyzes GTP found on Ras to inactivate it. If GAP is non-functional, Ras stays in the “on” position indefinitely.

Question 10

Tumor Suppressor Genes

Describe the features of HNPCC (hereditary non polyp colon cancer). Hint: think mismatch repair

Answer 10

If either both copies of MSH2 or MLH1 (both are enzymes involved in DNA mismatch repair) is mutated you will get the same type of cancer. This is because they are both involved in the same pathway.

Question 11

Name 5 examples of tumor suppressor genes

Answer 11

1) RB
2) p53
3) CKI (ie P16)
4) GAP
5) various DNA repair enzymes

Question 12

Draw a diagram of the steps of the PI-3 Kinase pathway, involving PTEN, mTOR, etc.

Answer 12