The Role of Drosophila Merlin in the Control of Mitosis Exit and Development
Annual rept. 1 Jul 2006-30 Jun 2007
CHILDRENS RESEARCH INST COLUMBUS OH
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To better understand the mechanism by which Merlin functions as a tumor suppressor we have shown that mutations in the Drosophila Merlin gene lead to increased mitosis and alter the duration of the G2 phase of the cell cycle. We have also found that the Merlin protein is dynamically redistributed during meiosis and discovered for the first time Merlin immunoreactivity in the mitochondria. In support of the finding of a genetic interaction between Merlin and lap which encodes an adapter protein involved in vesicular trafficking we show that both the Merlin and Lap proteins colocalize at the cellular cortex of the wing imaginal disc cell. In addition we demonstrate that the distribution of the Merlin protein in the wing imaginal disc is not affected by other tumor suppressor mutations. We also show that the Drosophila Merlin protein is regulated by phosphorylation while the non-phospho-Merlin protein appears mostly in the cytoplasm the phospho-Merlin protein can be seen in the membrane region. Furthermore we have found that the AKT pathway is frequently activated in NF2- tumor cells. We have tested two novel compounds OSU03012 and S-HDAC-42, which inhibit AKT phosphorylation. We show that these drugs effectively inhibit the growth of vestibular schwannoma cells. These findings set the stage for a phase 1 clinical trial on VS in the future.
- Genetic Engineering and Molecular Biology
- Anatomy and Physiology
- Medicine and Medical Research