Fem1b promotes ubiquitylation and suppresses transcriptional activity of Gli1.
The mammalian Fem1b gene encodes a homolog of FEM-1, a protein in the sex-determination pathway of the nematode Caenorhabditis elegans. Fem1b and FEM-1 proteins each contain a VHL-box motif that mediates their interaction with certain E3 ubiquitin ligase complexes. In C. elegans, FEM-1 negatively regulates the transcription factor TRA-1, and functions as an E3 ubiquitin ligase substrate recognition subunit to target TRA-1 for ubiquitylation. TRA-1 is homologous to the mammalian Gli1 protein, a transcription factor that mediates Hedgehog signaling as well as having Hedgehog-independent functions. Whether the interaction between nematode FEM-1 and TRA-1 proteins is conserved, between corresponding mammalian homologs, has not been reported. Herein, we show that Fem1b interacts with Gli1 within cells, and directly binds Gli1. Fem1b also promotes ubiquitylation of Gli1, suppresses transcriptional activation by Gli1, and attenuates an oncogenic Gli1 autoregulatory loop in cancer cells, all dependent on the VHL-box of Fem1b. These findings have implications for understanding the cellular functions of Fem1b, and the regulation of Gli1 oncoprotein activity.
['Gilder|Andrew S|AS|', 'Chen|Yong-Bin|YB|', 'Jackson|Ramon J|RJ|', 'Jiang|Jin|J|', 'Maher|Joseph F|JF|']
D000818:Animals D017173:Caenorhabditis elegans D029742:Caenorhabditis elegans Proteins D002352:Carrier Proteins D018797:Cell Cycle Proteins D004268:DNA-Binding Proteins D057809:HEK293 Cells D006801:Humans D047468:Immunoprecipitation D051741:Kruppel-Like Transcription Factors D051379:Mice D041681:NIH 3T3 Cells D009369:Neoplasms D014157:Transcription Factors D014158:Transcription, Genetic D043743:Ubiquitin-Protein Ligase Complexes D054875:Ubiquitination D000071676:Zinc Finger Protein GLI1
Fem1b Transcription Gli1 FEM-1 Ubiquitin TRA-1