Functional analysis of MEN1 in Drosophila model

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DESCRIPTION (provided by applicant): Analysis of the genes responsible for hereditary cancer predisposition and the pathways in which they act has been critically important in providing insight into the normal regulation of cell growth and differentiation. MEN1 is a hereditary disorder characterized by tumors of the parathyroids, pancreatic islets, and pituitary gland. The responsible gene encodes a nuclear protein, "menin", of unknown function. A Drosophila homolog of MEN1 was recently identified by the Berkeley Genome Project. In preliminary studies my laboratory showed that the gene is expressed in a variety of developing tissues including the major endocrine organs of the fly. We created transgenic flies with overexpression of Drosophila MEN1 and found that expression in the ectoderm Td a phenotype similar to that caused by mutations of Drosophila Jun. Genetic modifier studies showed an interaction between MEN1 and both Jun and Fos. In addition to the transgenic flies, we have now created a toss-of-function mutant of Drosophila MEN1. My preliminary results in conjunction with other reports indicate that menin acts in several different signal transduction pathways and in many different cellular and developmental processes. Biochemical studies have shown an interaction between menin and JunD, SMAD3, NF-kB, NM23 and Pem The fact that menin complexes with several transcription factors but does not itself bind DNA suggests that it may be a transcriptional co-modulator. Further genetic manipulations possible in a Drosophila model will allow me to study the function of menin in control of cellular differentiation and proliferation at any developmental stage. Genetic modifier screens in this invertebrate organism and expression profiting with microarrays wilt help identify the genetic pathways in which menin functions and the physiologic context in which each interaction is important. The experiments outlined in this proposal will determine if Drosophila menin functions as a co-repressor molecule, shed tight on the role of menin in development of somatic tissues and the germline and determine whether loss of menin leads to a hyperproliferative cellular phenotype I anticipate that many or all of the cellular functions of menin found in the Drosophila model will have counterparts in mammals. My future plans include targeted genetic interaction studies in the mouse, based on interactions discovered in the fly. Determining which genetic pathways are important in menin-related neoplasia wilt lay the groundwork for rational medical therapy.