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The Role of Drosophila Merlin in the Control of Mitosis Exit and Development

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Final rept. 1 Jul 2004-30 Jun 2008

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To better understand the mechanism by which Merlin functions as a tumor suppressor, we have confirmed that Drosophila Merlin plays important roles in the control of mitosis exit and in the determination of dorsalventral compartment border during wing imaginal disc development. We show that the Merlin protein is dynamically redistributed during meiosis and demonstrate, for the first time, Merlin immunoreactivity in mitochondria. Also, we have found that Merlin colocalizes with Wingless morphogen in the cells at the dorsalventral compartment border of the wing imaginal disc. Merlin inactivation may alter the determinationmaintenance of Wingless stripe expression. Cells lacking Merlin possess greater ability to overcome vein restriction. In addition, we provide evidence for potential genetic interactions between Merlin and the proteins involved in vesicular trafficking, including Porcupine, Shibire, and Lap. By analyzing the evolution, diversity, and overall distribution of Merlin among different taxa, we demonstrate a monophyletic origin of the Merlin proteins with their root in the early metazoa. The overall similarity among the primary and secondary structures of all merlin proteins and the conservation of several functionally important residues suggest a universal role for merlin in a wide range of metazoa. Furthermore, we show 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, and found that these drugs effectively inhibit the growth of vestibular schwannoma cells. These findings set the stage for a phase I clinical trial on VS in the future.

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  • Biochemistry
  • Medicine and Medical Research

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