title: EDD, the human hyperplastic discs protein, has a role in progesterone receptor coactivation and potential involvement in DNA damage response.
abstract: The ubiquitin-protein ligase EDD encodes an orthologue of the hyperplastic discs tumor suppressor gene, which has a critical role in Drosophila development. Frequent allelic imbalance at the EDD chromosomal locus in human cancers suggests a role in tumorigenesis. In addition to a HECT (homologous to E6-AP carboxyl terminus) domain, the EDD protein contains a UBR1 zinc finger motif and ubiquitin-associated domain, each of which indicates involvement in ubiquitinylation pathways. This study shows that EDD interacts with importin alpha 5 through consensus basic nuclear localization signals and is localized in cell nuclei. EDD also binds progesterone receptor (PR) and potentiates progestin-mediated gene transactivation. This activity is comparable with that of the coactivator SRC-1, but, in contrast, the interaction between EDD and PR does not appear to involve an LXXLL receptor-binding motif. EDD also binds calcium- and integrin-binding protein/DNA-dependent protein kinase-interacting protein, a potential target of ubiquitin-mediated proteolysis, and an altered association is found between EDD and calcium- and integrin-binding protein/DNA-dependent protein kinase-interacting protein in response to DNA damage. The data presented here demonstrate a role for EDD in PR signaling but also suggest a link to cancer through DNA damage response pathways.
authors: Cancer Research Program, Garvan Institute of Medical Research, St Vincent's Hospital, 384 Victoria Street, Darlinghurst, New South Wales 2010, Australia.
authors: Michelle J
authors: MJ
authors: Henderson
authors: Amanda J
authors: AJ
authors: Russell
authors: Samantha
authors: S
authors: Hird
authors: Marcia
authors: M
authors: Muñoz
authors: Jennifer L
authors: JL
authors: Clancy
authors: Gillian M
authors: GM
authors: Lehrbach
authors: Sophina T
authors: ST
authors: Calanni
authors: David A
authors: DA
authors: Jans
authors: Robert L
authors: RL
authors: Sutherland
authors: Colin K W
authors: CK
authors: Watts
mesh_terms: D000595:Amino Acid Sequence; D002135:Calcium-Binding Proteins; D002352:Carrier Proteins / Q000378:metabolism; D002460:Cell Line; D002467:Cell Nucleus / Q000502:physiology; D004249:DNA Damage; D006801:Humans; D008969:Molecular Sequence Data; D010453:Peptide Synthases / Q000502:physiology*; D010957:Plasmids; D011485:Protein Binding; D011980:Receptors, Progesterone / Q000378:metabolism*; D015533:Transcriptional Activation; D020798:Two-Hybrid System Techniques; D044767:Ubiquitin-Protein Ligases; D028901:alpha Karyopherins / Q000378:metabolism
chemical_list: C109198:CIB1 protein, human; D002135:Calcium-Binding Proteins; D002352:Carrier Proteins; C423142:KPNA1 protein, human; D011980:Receptors, Progesterone; D028901:alpha Karyopherins; C117617:UBR5 protein, human; D044767:Ubiquitin-Protein Ligases; D010453:Peptide Synthases