RGD Reference Report - The activating enzyme of NEDD8 inhibits steroid receptor function. - Rat Genome Database

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The activating enzyme of NEDD8 inhibits steroid receptor function.

Authors: Fan, M  Long, X  Bailey, JA  Reed, CA  Osborne, E  Gize, EA  Kirk, EA  Bigsby, RM  Nephew, KP 
Citation: Fan M, etal., Mol Endocrinol 2002 Feb;16(2):315-30.
RGD ID: 634396
Pubmed: PMID:11818503   (View Abstract at PubMed)
DOI: DOI:10.1210/mend.16.2.0778   (Journal Full-text)

Coregulator proteins, coactivators and corepressors, have a profound influence on steroid receptor activity and play a role in regulating receptor levels. To identify novel coregulators of nuclear receptors, we used the ligand-binding and hinge region of ERalpha as bait in a yeast two-hybrid screen of a cDNA library derived from rat uterine luminal epithelium. We report the cloning and characterization of a cDNA encoding a protein homologous to yeast and human ubiquitin-activating enzyme 3 (Uba3), the catalytic subunit of the activating enzyme of the ubiquitin-like NEDD8 (neural precursor cellexpressed developmentally down-regulated) conjugation pathway (known as neddylation). Sequence analysis revealed that Uba3 contains multiple nuclear receptor (NR)-interacting motifs (NR boxes), which are known to mediate interactions between coregulatory proteins and ligand-activated NRs. Yeast two-hybrid and glutathione-S-transferase pull-down assays demonstrated that Uba3 directly interacts with ligand-occupied ERalpha and ERbeta. Transient transfection of Uba3 in mammalian cells inhibited ER-mediated transactivation in a time-dependent fashion; Uba3 had no effect on the initial events of transcriptional activation by liganded ER, but it blocked the progressive increase in target gene expression during continuous stimulation. Uba3 also inhibited transactivation by AR and PR in mammalian cells but had no effect on a steroid receptor-independent transactivation pathway. An enzymatically silent form of Uba3 did not inhibit ER-induced transcription, and a Uba3-binding fragment of amyloid precursor protein-binding protein, the other subunit of the NEDD8-activating enzyme, partially overcame Uba3-mediated inhibition, demonstrating that the neddylation activity of Uba3 is required for its inhibition of steroid receptor transactivation. Thus, Uba3 inhibits transcription induced by steroid hormone receptors through a novel mechanism that involves the neddylation pathway. Understanding the mechanisms controlling hormone responsiveness of target tissues, such as the uterus and mammary gland, may lead to novel insights of therapeutic intervention.



Gene Ontology Annotations    Click to see Annotation Detail View

Biological Process

  
Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
Uba3Ratnegative regulation of DNA-templated transcription  IDA  RGD 
Uba3Ratprotein neddylation  TAS  RGD 

Molecular Function

  

Molecular Pathway Annotations    Click to see Annotation Detail View

RGD Manual Annotations


  
Objects Annotated

Genes (Rattus norvegicus)
Esr1  (estrogen receptor 1)
Ncoa3  (nuclear receptor coactivator 3)
Uba3  (ubiquitin-like modifier activating enzyme 3)

Genes (Mus musculus)
Uba3  (ubiquitin-like modifier activating enzyme 3)

Genes (Homo sapiens)
UBA3  (ubiquitin like modifier activating enzyme 3)


Additional Information