A Drosophila model of multiple endocrine neoplasia type 2.
作者： Renee D. Read , Paul J. Goodfellow , Elaine R. Mardis , Nancy Novak , Jon R. Armstrong
DOI: 10.1534/GENETICS.104.038018
关键词:
摘要: Dominant mutations in the Ret receptor tyrosine kinase lead to familial cancer syndrome multiple endocrine neoplasia type 2 (MEN2). Mammalian tissue culture studies suggest that RetMEN2 significantly alter Ret-signaling properties, but precise mechanisms by which promotes tumorigenesis remain poorly understood. To determine signal transduction pathways required for activity, we analyzed analogous Drosophila ortholog dRet. Overexpressed dRetMEN2 isoforms targeted developing retina led aberrant cell proliferation, inappropriate fate specification, and excessive Ras pathway activation. Genetic analysis indicated acts through Ras-ERK, Src, Jun pathways. A genetic screen dominantly suppress or enhance phenotypes identified new genes are phenotypic outcomes of activity. Finally, human orthologs many these examined their status tumors. Two loci showed loss heterozygosity (LOH) within both sporadic MEN2-associated pheochromocytomas, suggesting they may contribute Ret-dependent oncogenesis.
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