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- Title
A Drosophila Model of Multiple Endocrine Neoplasia Type 2.
- Authors
Read, Renee D.; Goodfellow, Paul J.; Mardis, Elaine R.; Novak, Nancy; Armstrong, Jon R.; Cagan, Ross L.
- Abstract
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 dRetMMEN2 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.
- Subjects
DROSOPHILA; PROTEIN-tyrosine kinases; CELLULAR signal transduction; CELL proliferation; GENE expression; GENETIC mutation
- Publication
Genetics, 2005, Vol 171, Issue 3, p1057
- ISSN
0016-6731
- Publication type
Article
- DOI
10.1534/genetics.104.038018