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• W2271490384 abstract "Mutations in the human EYA1 gene are associated with several congenital disorders, as for example BOR (branchio-oto-renal) syndrome. BOR patients suffer from severe malformations of the ear, the branchial arches and the kidneys. The mechanisms by which EYA1 mutations cause human disease are only poorly understood. Several disease-associated EYA1 mutations were characterized in this work regarding their effect on Eya1 protein function. Some of the mutations lead to enhanced proteasomal degradation of the protein in mammalian cells. Loss of Eya1 activity due to loss of Eya1 protein might represent a so far unknown mechanism for the onset of EYA1-associated diseases. Further analyses revealed that ubiquitination occurs in the C-terminus of Eya1 and is inhibited by interaction with Six1. These findings indicate that Six1 is involved in the regulation of Eya1 protein stability. A central aim of this work was the identification of novel Eya1-interacting proteins. Using yeast two-hybrid analysis two novel interaction partners were identified: Sipl1 and Rbck1. Binding studies demonstrated that the interaction is mediated via the C-terminus of Eya1 and the Ubl domain of Sipl1 or Rbck1, respectively. Furthermore, orthologs of Sipl1 and Rbck1 were identified in zebrafish. Sipl1 and Rbck1 are co-expressed with Eya1 in several organs during embryogenesis of both mouse and zebrafish. Interestingly, knockdown of one Sipl1 ortholog in zebrafish led to a BOR syndrome-like phenotype. The results of expression studies and knockdown analyses indicate that, indeed, the Eya1-Sipl1/Rbck1 interaction is of physiological relevance in the context of organ development. This hypothesis was underlined by the identification of SIPL1 and RBCK1 mutations in patients suffering from BOR syndrome. A first mechanistic basis was provided by results from transactivation studies showing that Sipl1 and Rbck1 enhance the function of Eya proteins to act as co-activators for the Six transcription factors." @default.
• W2271490384 created "2016-06-24" @default.
• W2271490384 creator A5063432504 @default.
• W2271490384 date "2009-01-13" @default.
• W2271490384 modified "2023-09-27" @default.
• W2271490384 title "Identification and characterization of Eya1-interacting proteins" @default.
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