The overall aim of this proposal is to determine whether Cux-1 is a downstream effector of the Notch signaling pathway. Cux-1 is the murine homologue of the Drosophila gene Cut. Mammalian Cut proteins function as cell cycle-dependent transcriptional repressors in many different tissues. Cux-1 represses the expression of the cyclin kinase inhibitor p21 in S phase and is part of the network controlling G1-S transition. Cux-1 also represses the CKI p27, and ectopic expression of Cux-1 in transgenic mice results in multiorgan hyperplasia from the aberrant down regulation of p27 expression. While much has been learned about the targets of Cux-1 regulation, little is known about the upstream regulators of Cux-1. In Drosophila, Cut functions as a downstream effector of the Notch signaling pathway. Preliminary studies show that Cux-1 is upregulated in rat kidney epithelial cells expressing a constitutively active Notch receptor, and this is associated with decreased expression of p27. In addition, immunoprecipitation assays reveal an interaction between Cux-1 and the groucho homologue TLE-4, a co-repressor that interacts with known effectors of Notch signaling. Finally, recent studies reveal a striking similarity in expression pattern between Cux-1 and Notch pathway components during kidney development. These results suggest that Cux-1 functions as an effector of the Notch signaling pathway. The proposed studies will test the hypothesis that regulation of Cux-1 by the Notch signaling pathway is conserved during mammalian development and that Cux-1 interacts with TLE proteins to regulate p27 gene expression.
The specific aims are: 1. Determine whether Notch signaling is required for Cux-1 expression. 2. Evaluate the interaction between TLE proteins and Cux-1. 3. Define the relationship between Cux-1 and Notch2 in kidney development in vivo. 4. Define the relationship between Cux-1, TLE-4, and Notch signaling during podocyte development and nephrogenesis. These studies will provide novel insights into the mechanisms of cell proliferation during development. ? ? ?
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