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Medical Sciences (M.F., X.L., J.A.B., C.A.R., E.O., E.A.K., K.P.N.), Indiana University School of Medicine, Bloomington, Indiana 47405; and Department of Obstetrics & Gynecology (X.L., R.M.B., K.P.N.) and Department of Cellular and Integrative Physiology (E.A.G., R.M.B., K.P.N.), Indiana University School of Medicine, Indianapolis, Indiana 46202
Address all correspondence and requests for reprints to: Kenneth P. Nephew, Ph.D., Medical Sciences, Indiana University School of Medicine, 302 Jordan Hall, 1001 East Third Street, Bloomington, Indiana 47405-4401. E-mail: knephew{at}indiana.edu
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 ER
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 ER and ERß.
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.
This article has been cited by other articles:
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 M. Fan, P. S. Yan, C. Hartman-Frey, L. Chen, H. Paik, S. L. Oyer, J. D. Salisbury, A. S.L. Cheng, L. Li, P. H. Abbosh, et al. Diverse Gene Expression and DNA Methylation Profiles Correlate with Differential Adaptation of Breast Cancer Cells to the Antiestrogens Tamoxifen and Fulvestrant Cancer Res., December 15, 2006; 66(24): 11954 - 11966. [Abstract] [Full Text] [PDF]
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M. Fan, H. Nakshatri, and K. P. Nephew Inhibiting Proteasomal Proteolysis Sustains Estrogen Receptor-{alpha} Activation Mol. Endocrinol., November 1, 2004; 18(11): 2603 - 2615. [Abstract] [Full Text] [PDF]
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 J. van der Spuy, J. H. Kim, Y. S. Yu, A. Szel, P. J. Luthert, B. J. Clark, and M. E. Cheetham The Expression of the Leber Congenital Amaurosis Protein AIPL1 Coincides with Rod and Cone Photoreceptor Development Invest. Ophthalmol. Vis. Sci., December 1, 2003; 44(12): 5396 - 5403. [Abstract] [Full Text] [PDF]
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