title: The Ajuba LIM domain protein is a corepressor for SNAG domain mediated repression and participates in nucleocytoplasmic Shuttling.
abstract: The SNAG repression domain is comprised of a highly conserved 21-amino acid sequence, is named for its presence in the Snail/growth factor independence-1 class of zinc finger transcription factors, and is present in a variety of proto-oncogenic transcription factors and developmental regulators. The prototype SNAG domain containing oncogene, growth factor independence-1, is responsible for the development of T cell thymomas. The SNAIL proteins also encode the SNAG domain and play key roles in epithelial mesenchymal differentiation events during development and metastasis. Significantly, these oncogenic functions require a functional SNAG domain. The molecular mechanisms of SNAG domain-mediated transcriptional repression are largely unknown. Using a yeast two-hybrid strategy, we identified Ajuba, a multiple LIM domain protein that can function as a corepressor for the SNAG domain. Ajuba interacts with the SNAG domain in vitro and in vivo, colocalizes with it, and enhances SNAG-mediated transcriptional repression. Ajuba shuttles between the cytoplasm and the nucleus and may form a novel intracellular signaling system. Using an integrated reporter gene combined with chromatin immunoprecipitation, we observed rapid, SNAG-dependent assembly of a multiprotein complex that included Ajuba, SNAG, and histone modifications consistent with the repressed state. Thus, SNAG domain proteins may bind Ajuba, trapping it in the nucleus where it functions as an adapter or molecular scaffold for the assembly of macromolecular repression complexes at target promoters.
authors.affiliation: The Wistar Institute, Philadelphia, Pennsylvania 19104-4268, USA.
authors.forename: Kasirajan
authors.initials: K
authors.lastname: Ayyanathan
authors.forename: Hongzhuang
authors.initials: H
authors.lastname: Peng
authors.forename: Zhaoyuan
authors.initials: Z
authors.lastname: Hou
authors.forename: William J
authors.initials: WJ
authors.lastname: Fredericks
authors.forename: Rakesh K
authors.initials: RK
authors.lastname: Goyal
authors.forename: Ellen M
authors.initials: EM
authors.lastname: Langer
authors.forename: Gregory D
authors.initials: GD
authors.lastname: Longmore
authors.forename: Frank J
authors.initials: FJ
authors.lastname: Rauscher
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D002467:Cell Nucleus / Q000378:metabolism; D003593:Cytoplasm / Q000378:metabolism; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D060588:LIM Domain Proteins; D051379:Mice; D008969:Molecular Sequence Data; D041681:NIH 3T3 Cells; D000072041:PAX3 Transcription Factor; D051761:Paired Box Transcription Factors / Q000235:genetics / Q000378:metabolism; D017434:Protein Structure, Tertiary; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic
chemical_list: D018398:Homeodomain Proteins; D060588:LIM Domain Proteins; D000072041:PAX3 Transcription Factor; D051761:Paired Box Transcription Factors; D012097:Repressor Proteins; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors; C485607:ajuba protein, mouse; C068686:Pax3 protein, mouse