Question

You are the Director of a company that specializes in cancer therapies.  The goal of your company is to develop drugs that will knockout the function of various proteins in the cell.  Evaluate & determine if the protein is considered a tumor suppressor or proto-oncogene. For each of the following targets, indicate if it would be a "good idea" or "bad idea" to develop a drug to knockout the function of the protein to target cancer (4 pts)

a) a drug that targets (knocks out function of) an IAP

Good                           Bad

b) a drug that targets (knocks out function of) MAD2

Good                           Bad

c) a drug that targets (knocks out function of) a GEF for Ras

Good                           Bad

d) a drug that targets (knocks out function of) MAPKK

Good                           Bad

Which of the above proteins would be considered proto-oncogenes & which would be considered tumor suppressors (4 pts?)   (You're answering for the PROTEIN, NOT THE DRUG. So, for example, is IAP an oncogene or tumor suppressor)

Briefly explain your answers.

Answer 1

a) Good, IAP is a proto oncogene

Inhibitors of apoptosis are a set of proteins which bind with several apoptotic proteins like caspase and arrest apoptosis. Blocking apoptosis can always trigger cancer. Hence this is an proto-oncogene (protein). If it's activity is not regulated properly and it constitutively blocks apoptosis then the gene can easily turn oncogenic. Hence, knocking it out will be a good therapeutic idea.

There are reported drugs like LCL 161 which reduce effects of IAP and help in treatment of cancer.

B) Bad. (MAD2 is a tumour suppressor gene)

MAD2 proteins are key proteins involved in spindle check point. They arrest progression of cells to anaphase from metaphase. So, MAD2 proteins are helping in stopping the cell division. Therefore, MAD2 proteins are tumour suppressor gene (protein). Mutating them will make progression of cells from metaphase to anaphase unhindered and hence cell will continuously divide and turn cancerous. Therefore, knocking it out will be a bad idea.

C, Good, Ras protein along with GEF is a proto oncogene.

Guanine exchange factor involved with Ras proteins is important for replacing GDP with GTP and switching on the Ras proteins and hence triggers the cell division. Constitutively active Ras proteins can trigger a downward signaling cascade which may result in cancer. Therefore, it is a proto oncogene (Protein). Mutating GEF involved with Ras will arrest replacement of GDP with GTP and hence, turn the signaling off. Therefore, it will be a good option to make it's knock out.

D. Good -MAPKK.is a proto oncogene

Mitogen activated protein kinase kinases are involved in phosphorylating mitogen activated protein kinase (MAPK). MAPK. MAPK proteins are involved in cell division and cell differentiation. Constitutively activated MAPKK will continue to phosphorylate the MAPK and hence, cell division will be continuous. Therefore, MAPKK is a proto oncogene. (Protein) Knocking it out will be of therapeutic value in cancer patients.

In fact MAPK signaling has been reported to be constitutively activated in number of myeloma cells.