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.
Cancer Institute and Department of Medicine, University of Mississippi Medical Center, Jackson, MS 39216, United States.
Andrew S
AS
Gilder
Yong-Bin
YB
Chen
Ramon J
RJ
Jackson
Jin
J
Jiang
Joseph F
JF
Maher
D000818:Animals; D017173:Caenorhabditis elegans / Q000378:metabolism; D029742:Caenorhabditis elegans Proteins / Q000235:genetics / Q000378:metabolism; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D047468:Immunoprecipitation; D051741:Kruppel-Like Transcription Factors / Q000235:genetics / Q000378:metabolism; D051379:Mice; D041681:NIH 3T3 Cells; D009369:Neoplasms / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic; D043743:Ubiquitin-Protein Ligase Complexes; D054875:Ubiquitination; D000071676:Zinc Finger Protein GLI1
D029742:Caenorhabditis elegans Proteins; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; C115306:FEM-1 protein, C elegans; C403492:FEM1B protein, human; C400551:GLI1 protein, human; C498520:Gli1 protein, mouse; D051741:Kruppel-Like Transcription Factors; D014157:Transcription Factors; D000071676:Zinc Finger Protein GLI1; C121025:tra-1 protein, C elegans; C498596:Fem1b protein, mouse; D043743:Ubiquitin-Protein Ligase Complexes
FEM-1; Fem1b; Gli1; TRA-1; Transcription; Ubiquitin