title: The LIM domain protein LMO4 interacts with the cofactor CtIP and the tumor suppressor BRCA1 and inhibits BRCA1 activity.
abstract: LMO4 belongs to the LIM-only (LMO) group of transcriptional regulators that appear to function as molecular adaptors for protein-protein interactions. Expression of the LMO4 gene is developmentally regulated in the mammary gland and is up-regulated in primary breast cancers. Using LMO4 in a yeast two-hybrid screen, we have identified the cofactor CtIP as an LMO4-binding protein. Interaction with CtIP appeared to be specific for the LMO subclass of LIM domain proteins and could be mediated by a single LIM motif of LMO4. We further identified the breast tumor suppressor BRCA1 as an LMO4-associated protein. The C-terminal BRCT domains of BRCA1, previously shown to bind CtIP, also mediated interaction with LMO4. Tumor-associated mutations within the BRCT repeats that abolish interaction between BRCA1 and CtIP had no effect on the association of BRCA1 with LMO4. A stable complex comprising LMO4, BRCA1, and CtIP was demonstrated in vivo. The LIM domain binding-protein Ldb1 also participated in this multiprotein complex. In functional assays, LMO4 was shown to repress BRCA1-mediated transcriptional activation in both yeast and mammalian cells. These findings reveal a novel complex between BRCA1, LMO4, and CtIP and indicate a role for LMO4 as a repressor of BRCA1 activity in breast tissue.
authors.affiliation: Walter and Eliza Hall Institute of Medical Research and Bone Marrow Research Laboratories, Melbourne, Victoria 3050, Australia.
authors.forename: Eleanor Y M
authors.initials: EY
authors.lastname: Sum
authors.forename: Benjamin
authors.initials: B
authors.lastname: Peng
authors.forename: Xin
authors.initials: X
authors.lastname: Yu
authors.forename: Junjie
authors.initials: J
authors.lastname: Chen
authors.forename: Jennifer
authors.initials: J
authors.lastname: Byrne
authors.forename: Geoffrey J
authors.initials: GJ
authors.lastname: Lindeman
authors.forename: Jane E
authors.initials: JE
authors.lastname: Visvader
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D019313:BRCA1 Protein / Q000737:chemistry / Q000378:metabolism*; D015152:Blotting, Northern; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000378:metabolism; D002352:Carrier Proteins / Q000737:chemistry / Q000378:metabolism*; D002455:Cell Division; D002460:Cell Line; D018076:DNA, Complementary / Q000378:metabolism; D004706:Endodeoxyribonucleases; D004847:Epithelial Cells / Q000378:metabolism; D018398:Homeodomain Proteins / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D060588:LIM Domain Proteins; D009687:Nuclear Proteins / Q000737:chemistry / Q000378:metabolism*; D010957:Plasmids / Q000378:metabolism; D011233:Precipitin Tests; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D014157:Transcription Factors / Q000737:chemistry / Q000378:metabolism*; D015533:Transcriptional Activation; D020798:Two-Hybrid System Techniques
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D019313:BRCA1 Protein; D002352:Carrier Proteins; D018076:DNA, Complementary; D018398:Homeodomain Proteins; D060588:LIM Domain Proteins; C114905:LMO4 protein, human; D009687:Nuclear Proteins; D011993:Recombinant Fusion Proteins; D014157:Transcription Factors; D004706:Endodeoxyribonucleases; C410741:RBBP8 protein, human