Sumoylation differentially regulates Goosecoid-mediated transcriptional repression.
Goosecoid (Gsc), a paired-like homeobox gene expressed in the vertebrate organizer, functions as a transcriptional repressor either by direct DNA binding to paired TAAT homeodomain sites or through recruitment by the forkhead/winged helix transcription factor Foxh1. Here, we report that Gsc is post-translationally modified by small ubiquitin-like modifier proteins (SUMO). Members of the PIAS family of proteins enhance Gsc sumoylation and this modification occurs on at least six lysine residues. Stable expression of a SUMO-defective Gsc mutant (Gsc 6Km) in MDA-MB-231 breast cancer cells results in morphological changes giving rise to cells with increased cell area. We demonstrate that Gsc 6Km can effectively repress Foxh1-mediated induction of the Mixl1 promoter, indicating that sumoylation is not required for Gsc-mediated repression of promoters where recruitment occurs through Foxh1. In contrast, Gsc 6Km exhibits a decreased ability to repress the induction of promoters to which it is directly recruited through paired-homeodomain binding sites, including its own promoter and that of the Xenopus Brachyury gene. Taken together, our data suggests that regulation of Gsc repressive activity by SUMO modification is promoter specific and may serve to differentially regulate genes that function to control cell morphology during early development and cancer.
Izzi
Luisa
L
Department of Medical Biophysics, Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, 160 College Street, Toronto, Ontario Canada M5S 3E1.
Narimatsu
Masahiro
M
Attisano
Liliana
L
D000595:Amino Acid Sequence; D000818:Animals; D019556:COS Cells; D045744:Cell Line, Tumor; D048429:Cell Size; D002522:Chlorocebus aethiops; D051956:Goosecoid Protein / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008239:Lysine / Q000235:genetics; D051379:Mice; D008957:Models, Genetic; D008969:Molecular Sequence Data; D050505:Mutant Proteins / Q000378:metabolism; D009154:Mutation / Q000235:genetics; D011401:Promoter Regions, Genetic / Q000235:genetics; D050828:Protein Inhibitors of Activated STAT / Q000378:metabolism; D011499:Protein Processing, Post-Translational; D012097:Repressor Proteins / Q000378:metabolism*; D025841:Small Ubiquitin-Related Modifier Proteins / Q000378:metabolism*; D014158:Transcription, Genetic; D014981:Xenopus
D051956:Goosecoid Protein; D050505:Mutant Proteins; D050828:Protein Inhibitors of Activated STAT; D012097:Repressor Proteins; D025841:Small Ubiquitin-Related Modifier Proteins; D008239:Lysine