A Drosophila model of multiple endocrine neoplasia type 2.
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.
Read
Renee D
RD
Department of Genetics, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
Goodfellow
Paul J
PJ
Mardis
Elaine R
ER
Novak
Nancy
N
Armstrong
Jon R
JR
Cagan
Ross L
RL
D000595:Amino Acid Sequence; D000818:Animals; D004195:Disease Models, Animal; D004330:Drosophila / Q000235:genetics* / Q000254:growth & development; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism; D008969:Molecular Sequence Data; D018813:Multiple Endocrine Neoplasia Type 2a / Q000235:genetics*; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D051096:Proto-Oncogene Proteins c-ret / Q000235:genetics / Q000378:metabolism; D016392:Proto-Oncogene Proteins pp60(c-src) / Q000235:genetics / Q000378:metabolism; D012160:Retina / Q000254:growth & development / Q000378:metabolism; D018631:ras Proteins / Q000235:genetics / Q000378:metabolism
D020033:Protein Isoforms; D051096:Proto-Oncogene Proteins c-ret; C099282:RET protein, human; D016392:Proto-Oncogene Proteins pp60(c-src); D048031:JNK Mitogen-Activated Protein Kinases; D018631:ras Proteins