EDD, the human hyperplastic discs protein, has a role in progesterone receptor coactivation and potential involvement in DNA damage response.
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.
Henderson
Michelle J
MJ
Cancer Research Program, Garvan Institute of Medical Research, St Vincent's Hospital, 384 Victoria Street, Darlinghurst, New South Wales 2010, Australia.
Russell
Amanda J
AJ
Hird
Samantha
S
Muñoz
Marcia
M
Clancy
Jennifer L
JL
Lehrbach
Gillian M
GM
Calanni
Sophina T
ST
Jans
David A
DA
Sutherland
Robert L
RL
Watts
Colin K W
CK
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
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