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Modern Genetic Analysis Chapter 15. Regulation of Cell Number: Normal and Cancer Cells
Problems

1.

Cancer is thought to be caused by the accumulation of two or more "hits"that is, two or more mutations affecting cell proliferation and survival within the same cell. Many of these oncogenic mutations are dominant: one mutant copy of the pertinent gene is sufficient to change the proliferative properties of a cell. Which of the following general types of mutations have the potential to be dominant oncogenes? Justify each answer.
a. A mutation increasing the number of copies of a transcriptional activator of cyclin A.
b. A nonsense mutation occurring shortly after the beginning of translation in a gene encoding a growth-factor receptor.
c. A mutation increasing the level of FasL.
d. A mutation that disrupts the active site of a cytoplasmic tyrosine-specific protein kinase.
e. A translocation joining a gene encoding an inhibitor of apoptosis to an enhancer element for gene expression in the liver.

2. | Many of the proteins that participate in the cell cycle progression pathway are reversibly modified, whereas, in the apoptosis pathway, the modification events are irreversible. Rationalize these observations in relation to the nature and end result of the two pathways.

3.

Normally, FasL is present on cells only when an instruction needs to be sent to neighboring cells for them to undergo apoptosis. Suppose that you have a mutation that produces FasL on the cell surface on all liver cells.
a. If the mutation were present in the germ line, would you predict such a mutation to be dominant or recessive?
b. If such a mutant arose in somatic tissues, would you expect it to be tumor promoting? Why or why not?

See answer

4. | Provide three types of evidence that cancer is a genetic disease. See answer

5. | Some genes can be mutated to become oncogenes by increasing the copy number of the gene. This, for example, is true of the Myc transcription factor. On the other hand, oncogenic mutations of ras are always point mutations that alter the protein structure of Ras. Rationalize these observations in relation to the roles of normal and oncogenic versions of Ras and Myc.

6. | We now understand that mutations that cause the inhibition of apoptosis are found in tumors. Because proliferation per se is not induced by the inhibition of apoptosis, explain how this inhibition might contribute to tumor formation. See answer

7.

Suppose that you had the ability to introduce normal copies of a gene into a tumor cell that had mutations in the gene that caused it to promote tumor growth.
a. If the mutations were in a tumor-suppressor gene, would you expect that these normal transgenes would block the tumor-promoting activity of the mutations? Why or why not?
b. If the mutations were of the oncogene type, would you expect that the normal transgenes would block their tumor-promoting activity? Why or why not?

8.

Insulin is a protein that is secreted by the pancreas (an endocrine organ) when blood sugar levels are high. Insulin acts on many distant tissues by binding and activating a receptor tyrosine kinase (RTK), leading to a reduction in blood sugar by appropriately storing the products of sugar metabolism.

Diabetes is a disease in which blood sugar levels remain high because some aspect of the insulin pathway is defective. One kind of diabetes (let's call this type A) can be treated by giving the patient insulin. Another kind of diabetes (call it type B) is not ameliorated by insulin treatment.
a. Which type of diabetes is likely to be due to a defect in the pancreas, and which type is likely to be due to a defect in the target cells? Justify your answer.
b. Type B diabetes can be due to mutations in any of several different genes. Explain this observation.

9. | Irreparable DNA damage can have consequences for both the cell cycle and apoptosis. Explain what the consequences are, as well as the pathways by which the cell implements them. See answer

© 1999 by W. H. Freeman and Company. All rights reserved.