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Originally published as Genetics Published Articles Ahead of Print on June 18, 2005.
Genetics, Vol. 171, 1057-1081, November 2005, Copyright © 2005
doi:10.1534/genetics.104.038018
A Drosophila Model of Multiple Endocrine Neoplasia Type 2
Renee D. Read*,
Paul J. Goodfellow
,
,
Elaine R. Mardis,
Nancy Novak,
Jon R. Armstrong and
Ross L. Cagan*,1
* Department of Molecular Biology and Pharmacology, Department of Surgery and Department of Genetics, Washington University School of Medicine, St. Louis, Missouri 63110
1 Corresponding author: Department of Molecular Biology and Pharmacology, Washington University School of Medicine, 660 S. Euclid Ave., St. Louis, MO 63110.
E-mail: cagan{at}wustl.edu
Dominant mutations in the Ret receptor tyrosine kinase lead to the familial cancer syndrome multiple endocrine neoplasia type 2 (MEN2). Mammalian tissue culture studies suggest that RetMEN2 mutations significantly alter Ret-signaling properties, but the precise mechanisms by which RetMEN2 promotes tumorigenesis remain poorly understood. To determine the signal transduction pathways required for RetMEN2 activity, we analyzed analogous mutations in the Drosophila Ret ortholog dRet. Overexpressed dRetMEN2 isoforms targeted to the developing retina led to aberrant cell proliferation, inappropriate cell fate specification, and excessive Ras pathway activation. Genetic analysis indicated that dRetMEN2 acts through the Ras-ERK, Src, and Jun kinase pathways. A genetic screen for mutations that dominantly suppress or enhance dRetMEN2 phenotypes identified new genes that are required for the phenotypic outcomes of dRetMEN2 activity. Finally, we identified human orthologs for many of these genes and examined their status in human tumors. Two of these loci showed loss of heterozygosity (LOH) within both sporadic and MEN2-associated pheochromocytomas, suggesting that they may contribute to Ret-dependent oncogenesis.
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