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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.

Pubmed ID: 12011095

Authors

  • Henderson MJ
  • Russell AJ
  • Hird S
  • Muñoz M
  • Clancy JL
  • Lehrbach GM
  • Calanni ST
  • Jans DA
  • Sutherland RL
  • Watts CK

Journal

The Journal of biological chemistry

Publication Data

July 19, 2002

Associated Grants

None

Mesh Terms

  • Amino Acid Sequence
  • Calcium-Binding Proteins
  • Carrier Proteins
  • Cell Line
  • Cell Nucleus
  • DNA Damage
  • Humans
  • Molecular Sequence Data
  • Peptide Synthases
  • Plasmids
  • Protein Binding
  • Receptors, Progesterone
  • Transcriptional Activation
  • Two-Hybrid System Techniques
  • Ubiquitin-Protein Ligases
  • alpha Karyopherins