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First published online 28 September 2005
doi: 10.1242/dev.02048

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DNA-binding domain mutations in SMAD genes yield dominant-negative proteins or a neomorphic protein that can activate WG target genes in Drosophila

Norma T. Takaesu¹, Eric Herbig^1,*, David Zhitomersky², Michael B. O'Connor² and Stuart J. Newfeld^1,

¹ School of Life Sciences, Arizona State University, Tempe, AZ 85287-4501, USA
² Howard Hughes Medical Institute, Department of Genetics, Cell Biology and Development, University of Minnesota, Minneapolis, MN 55455, USA

Author for correspondence (e-mail: newfeld{at}asu.edu)

Accepted 18 August 2005

Mutations in SMAD tumor suppressor genes are involved in approximately 140,000 new cancers in the USA each year. At this time, how the absence of a functional SMAD protein leads to a tumor is unknown. However, clinical and biochemical studies suggest that all SMAD mutations are loss-of-function mutations. One prediction of this hypothesis is that all SMAD mutations cause tumors via a single mechanism. To test this hypothesis, we expressed five tumor-derived alleles of human SMAD genes and five mutant alleles of Drosophila SMAD genes in flies. We found that all of the DNA-binding domain mutations conferred gain-of-function activity, thereby falsifying the hypothesis. Furthermore, two types of gain-of-function mutation were identified – dominant negative and neomorphic. In numerous assays, the neomorphic allele SMAD4^100T appears to be capable of activating the expression of WG target genes. These results imply that SMAD4^100T may induce tumor formation by a fundamentally different mechanism from other SMAD mutations, perhaps via the ectopic expression of WNT target genes – an oncogenic mechanism associated with mutations in Adenomatous Polyposis Coli. Our results are likely to have clinical implications, because gain-of-function mutations may cause tumors when heterozygous, and the life expectancy of individuals with SMAD4^100T is likely to be different from those with other SMAD mutations. From a larger perspective, our study shows that the genetic characterization of missense mutations, particularly in modular proteins, requires experimental verification.

Key words: Drosophila, SMAD genes, TGFß, Tumorigenesis, Pancreatic cancer, Colon cancer

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