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...

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Bibliographic Details
Published in:The Journal of biological chemistry 2002-07, Vol.277 (29), p.26468-26478
Main Authors: Henderson, Michelle J., Russell, Amanda J., Hird, Samantha, Muñoz, Marcia, Clancy, Jennifer L., Lehrbach, Gillian M., Calanni, Sophina T., Jans, David A., Sutherland, Robert L., Watts, Colin K.W.
Format: Article
Language:English
Subjects:
alpha Karyopherins - metabolism
Amino Acid Sequence
Calcium-Binding Proteins
Carrier Proteins - metabolism
Cell Line
Cell Nucleus - physiology
DNA Damage
Humans
Molecular Sequence Data
Peptide Synthases - physiology
Plasmids
Protein Binding
Receptors, Progesterone - metabolism
Transcriptional Activation
Two-Hybrid System Techniques
Ubiquitin-Protein Ligases
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Summary: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 carboxylterminus) 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 α5 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.
ISSN:0021-9258
1083-351X
DOI:10.1074/jbc.M203527200