Abstract 760: Fem1b attenuates the transcriptional activity of Gli1 by promoting the ubiquitin mediated degradation of Gli1.

Abstract

Abstract Gli1 is a member of the Gli family of zinc finger transcription factors that functions in stem cell biology, and as an oncogene in malignant transformation. The Hedgehog signaling pathway in flies and mammals shares homology to the sex determination pathway of C. elegans in which the Gli-like transcription factor TRA-1 is regulated by the ubiquitin ligase adapter FEM-1. Here we provide evidence that the mammalian FEM-1 homolog Fem1b regulates Gli1 transcriptional activity. Consistent with this, we demonstrate an interaction between Fem1b and Gli1, and show that Fem1b promotes the ubiquitylation and proteasome-mediated degradation of Gli1. Fem1b mediated ubiquitylation of Gli1 was dependent on the VHL box domain of Fem1b, shown to interact with Elongin B/C-Cul2-box protein ubiquitin ligases. Fem1b reduced Gli1 transcriptional activity in a reporter assay, and this reduction was also dependent on the VHL box of Fem1b. Given that Gli1 up-regulation promotes tumorigenesis in glioblastoma, medulloblastoma, basal cell carcinoma, and a variety of epithelial malignancies, we hypothesize that Fem1b antagonizes the oncogenic capacity of Gli1 by targeting Gli1 for ubiquitin-mediated destruction in the proteasome. Citation Format: Andrew S. Gilder, Deyin Lu, Joseph F. Maher. Fem1b attenuates the transcriptional activity of Gli1 by promoting the ubiquitin mediated degradation of Gli1. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 760. doi:10.1158/1538-7445.AM2013-760