Question

Part IV—The APC Protein

“Sam, I’m really worried about seeing my test results today,” Jane said as they headed in for another visit with their genetic counselor. “After Ms. Meeker explained your results to us, I’ve been dreading hearing whether or not I have the mutation too.”

Sam nodded, saying, “I can understand how you feel. I’m glad I can be here at the appointment to support you. Whatever happens, you know your family is here for you.”

Ms. Meeker arrived in the waiting room. “Jane and Sam, I’m glad you’re here. Please come in and let’s
talk,” she said, leading them into her office. “I’m sorry Jane, but your genetic testing results show that you inherited the same mutation in the APC gene that Sam has. As we discussed earlier, familial adenomatous polyposis, or FAP, is caused by a mutation in the APC gene. You inherited one normal copy and one mutant copy of the APC gene, and because of that, you are one step closer to cancer than a person who inherited two good copies of the gene. If the remaining good copy of the APC gene in your cells is damaged, this will lead to the development of colon cancer.”

Sam wrapped Jane in a bear hug. “I don’t know what to think,” Jane replied. “I guess I’m feeling numb. What is it about this APC protein that connects it to cancer? And what am I supposed to do next?”

“If you like, we can talk more about what APC does, and why this protein is important for control of cell growth,” Ms. Meeker offered. “And, I’d like to talk with you sometime soon about what we would recommend you should do next for your health management.”

“Why don’t we start with some more information about the APC protein,” Ms. Meeker continued. “APC interacts with and binds to other proteins in the cell. The APC protein is large, and we know that there are sub-regions within this protein. Each sub-region is specialized for binding to some other different protein.

When APC binds to other proteins, it influences the function of these other proteins. I have two figures to show you that I think will help make this clearer. Let me walk you through them,” she said as she handed

Jane and Sam a printout of two figures.

The two figures that Ms. Meeker presented to Jane and Sam are shown below. Figure 1 is a description of the APC protein domains, including which regions of APC are known to bind to other proteins. Figure 2 is a

diagram showing one of APC’s cellular functions. Examine these figures and then use the information you learn from them to answer the questions that follow.

“Colon Cancer” by Anne M. Casper Page 6

Questions

1. Would you expect Jane and Sam’s APC mutation to increase or decrease the ability of the APC protein to bind to -catenin?

2. If the remaining normal APC gene is damaged in one of Jane’s cells, how would this affect -catenin in that cell? How could this change affect the growth of that cell?

3. What are three categories of genes that when mutated can lead to tumor formation? Describe the characteristics of each category.

4. In which of these three categories would you classify APC? How would you classify -catenin?

5. Based on what you learned in this case study, what do you think Ms. Meeker would recommend that

   Jane do to manage her condition?

Answer 1

Solution:

The adenomatous polyposis coli (APC) protein is a major component in the Wnt signalling pathway. In this important signalling pathway, the APC negatively regulates the cellular proliferation by inhibiting an important downstream component in this pathway called, β-catenin. In the absence of APC's, the β-catenin along with Turnery complex factors (TCF) enter the nucleus and act as transcription factors for the production of different proteins which enhances cell division. Jane and Sam’s APC mutation decreased the ability of the APC protein to bind and inhibits the un wanted activation of β-catenin.

Presently the heterozygous recessive mutation in APC gene decreases their ability to bind and inhibit the unwanted activation of β-catenin in cells. Further damage to the remaining normal allele will change the mutation into complete recessive loss of function mutation and this APC completely fails to control β-catenin activation in cells. This will definitely lead to un controlled cell division.

The mutation affected to proto-oncogenes and tumour suppresser genes may lead to tumor formation. Dominant gain of function mutation to proto-oncogenes con verts it into oncogenes (eg: RAS gene), which activates unwanted cell proliferation. The mutation affected to tumour suppressor proteins like p53 and Rb called as recessive loss of function mutation, may also leads to the formation of tumours.