Characterization of a Novel Mechanism of Merlin-Associated Post-Transcriptional Gene Regulation
Abstract
Neurofibromatosis Type II or NF2 is a crippling cancer primarily affecting the nervous system. NF2 is an inherited genetic disease. NF2 patients are often born with one normal and one mutated copy of the NF2 gene. When the second copy of NF2 becomes mutated, tumors repeatedly develop in the brain and spinal cord. The NF2 gene encodes a protein called Merlin. We know that within all cells, Merlin functions as a tumor suppressor, a functional designation for a special class of proteins that instruct cells "not to divide." Merlin also has a second function, in that it also helps cells to "stick together," a critical activity needed to form various organs within our bodies. Our research focuses on determining why it is that Merlin is found in almost all cells that make up the human body, but mutations affecting the NF2 gene (encoding the Merlin protein) cause disease only in the brain and spinal cord with some peripheral nerve defects. Most groups are studying Merlin functions in isolated human cells. Experiments using isolated cells are limiting in that it is relatively difficult to assess how Merlin is causing cells to adhere to one another to form tissues. Animal studies are vastly preferable but are relatively difficult to do using vertebrates such as mice. At the crossroads between "simple" and "animal studies" is the well-established genetic model Drosophila or the fruit fly. Using flies, we have shown that Merlin needs other proteins to perform many of its functions. Using our fly model, we have already found several that work with Merlin, one of which, eIF4E-3, is only active in the nervous system or brain. Highly related forms of these genes are also found in humans. The eIF4E-3 partner protein of Merlin functions as an initial protein required to make protein from mRNA. This protein can control whether a protein is made or not made. This suggests that Merlin may work in ways we had not previously known. Our goal is to understand how this group of genes functions with Merlin to control how cells grow and stick together in the nervous system in order to aid development of improved diagnosis and therapies for NF2 tumors. Importantly, we have now shown that the conserved proteins in mammals, Merlin and eIF4E-1b also form a complex in rat brains and rat Schwann cells, are found together in the same part of the cell, and appear to regulate the same targets as we find in the fruit fly model. This is very exciting at it suggests the same novel mechanism of Merlin function will be completely conserved in mammals. Thus, once we determine how this is occurring in Drosophila and the proteins that are required, we can then translate our findings to test the similar proteins in mammalian models to confirm the same mechanism is occurring. We can then test patient tumor samples to show that defects in the proteins working with Merlin are missing or mutated. In addition, we can show that the production of specific proteins is not occurring as normal, which in turn affect how neural or neural associated cells grow. This study has the potential to establish a completely new line of research and opportunity to develop RNA-based therapies. This also opens up the exciting opportunity to develop small molecule inhibitors of eIF4E proteins that would be specific for eIF4E-3 (and the human homologue) identified in our studies. Currently, small molecule inhibitors for eIF4E protein are being used in clinical trials for other types of cancer and thus provide a very promising avenue to follow for the treatment of NF2-associated tumors.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 31, 2017
- Source ID
- W81XWH1610111
Entities
People
- Sarah Hughes
Organizations
- United States Army
- University of Alberta