Sipa1 is a candidate for underlying the metastasis efficiency modifier locus Mtes1
| Autor: | Mindy Lancaster, Kent W. Hunter, Douglas R. Lowy, Xiaohong Zhao, Paul D.P. Pharoah, Xiaolan Qian, Yeong-Gwan Park, Fabienne Lesueur |
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| Rok vydání: | 2005 |
| Předmět: |
Nonsynonymous substitution
Transcriptional Activation Candidate gene GTPase-activating protein Locus (genetics) Biology Genome Article Metastasis Mice Chlorocebus aethiops Genetics medicine Cell Adhesion Animals Humans Neoplasm Metastasis RNA Small Interfering Cell adhesion Polymorphism Genetic GTPase-Activating Proteins Nuclear Proteins medicine.disease rap GTP-Binding Proteins COS Cells Mutation Cancer research Biological Assay Signal transduction |
| Zdroj: | Nature genetics. 37(10) |
| ISSN: | 1061-4036 |
| Popis: | Previously, using an inbred strain screen and QTL mapping strategies, we demonstrated the presence of loci in the mouse genome that significantly influenced the ability of a transgene-induced mammary tumor to metastasize to the lung. Here we present data supporting the signal transduction molecule, Sipa1, as a candidate for the metastasis efficiency modifier locus Mtes1. Sequence analysis of genes in a candidate haplotype block revealed a non-synonymous animo acid polymorphism in the Sipa1 PDZ protein-protein interaction domain. Biochemical analysis indicates that the missense substitution had a significant effect on the Sipa1 RapGAP function. Spontaneous metastasis assays using cells expressing ectopic Sipa1 or Sipa1 shRNA to modulate the expression of Sipa1demonstrate that the metastatic capacity of a highly aggressive mouse mammary tumor cell line is correlated with cellular Sipa1 levels. Examination of human gene expression data is consistent with the role of Sipa1 concentration in metastatic progression. Together these data suggest that the PDZ domain polymorphism is likely to be at least one of the underlying genetic polymorphisms responsible for the Mtes1 locus. This is also, to the best of our knowledge, the first demonstration of a constitutional genetic polymorphism having a significant impact on tumor metastasis. |
| Databáze: | OpenAIRE |
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