Grant: CIHR Fellowship

The ribosome, an assembly consisting of protein and ribonucleic acid (RNA) components, is responsible for the production of proteins in human cells. Protein production is highly regulated and tightly controlled in human cells. However, sometimes the ribosome can become misregulated, which is associated with several types of cancer. Recently, an enzyme known as MINA53 was found to modify proteins that make up the ribosome. The expression level of MINA53 is higher than normal in many cancer types, such as lung, liver and colon cancers. The high expression level of this enzyme has been correlated to poor prognosis. Furthermore, if the level of MINA53 is suppressed, the growth of cancer cells is decreased. The goal of this research is to develop molecules that inhibit the activity of MINA53. These inhibitors should prevent MINA53 from modifying ribosomal proteins, allowing us to study the importance of this modification in cancer cells. If these inhibitors decrease the proliferation of cancer cells, they may also have therapeutic potential. We will use a bioengineered system to generate a library of peptides, and identify those that bind most strongly to MINA53. I will chemically synthesize sufficient amounts of these peptides, and test how strongly they inhibit MINA53 activity. I will then attempt to determine the three-dimensional structure of MINA53 bound to the peptide inhibitors. Based on this structure, it may be possible to design an inhibitor with increased potency and superior stability. With these optimized inhibitors, I will test their effect on several different cancer types to see their effect on cancer cell proliferation. To further examine the inhibitor activity in these cancer cells, I will purify the ribosomal proteins to determine the extent to which they are modified. These results will highlight the role of MINA53 in different cancers, and the inhibitors may lead to the development of new anticancer therapeutics.