The NEDD8 pathway is required for proteasome-mediated degradation of human estrogen receptor (ER)-α and essential for the antiproliferative activity of ICI 182,780 in ERα-positive breast cancer cells

Meiyun Fan, Robert M. Bigsby, Kenneth P. Nephew

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102 Citations (Scopus)

Abstract

Steroid hormone receptors, including estrogen receptor-α (ERα), are ligand-activated transcription factors, and hormone binding leads to depletion of receptor levels via preteasome-mediated degradation. NEDD8 (neural precursor cell-expressed developmentally down-regulated) is an ubiquitin-like protein essential for protein processing and cell cycle progression. We recently demonstrated that ubiquitin-activating enzyme (Uba)3, the catalytic subunit of the NEDD8-activating enzyme, inhibits ERα transcriptional activity. Here we report that Uba3-mediated inhibition of ERα transactivation function is due to increased receptor protein turnover. Coexpression of Uba3 with ERα increased receptor degradation by the 26S proteasome. Inhibition of NEDD8 activation and conjugation diminished polyubiquitination of ERα and blocked proteasome-mediated degradation of receptor protein. The antiestrogen ICI 182,780 is known to induce ER degradation. In human MCF7 breast cancer cells modified to contain a disrupted NEDD8 pathway, ICI 182,780 degradation of ERα was impaired, and the antiestrogen was ineffective at inhibiting cell proliferation. This study provides the first evidence linking nuclear receptor degradation with the NEDD8 pathway and the ubiquitin-proteasome system, suggesting that the two pathways can act together to modulate ERα turnover and cellular responses to estrogens. Based on our observation that an intact NEDD8 pathway is essential for the antiproliferation activity of the ICI 182,780 in ERα positive breast cancer cells, we propose that disruptions in the NEDD8 pathway provide a mechanism by which breast cancer cells acquire antiestrogen resistance while retaining expression of ERα.

Original languageEnglish (US)
Pages (from-to)356-365
Number of pages10
JournalMolecular Endocrinology
Volume17
Issue number3
DOIs
StatePublished - Mar 1 2003

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Proteasome Endopeptidase Complex
Estrogen Receptors
Breast Neoplasms
Estrogen Receptor Modulators
Ubiquitin-Activating Enzymes
Ubiquitins
fulvestrant
Hormones
Cell Cycle Proteins
Steroid Receptors
Cytoplasmic and Nuclear Receptors
Ubiquitin
Transcriptional Activation
Proteolysis
Catalytic Domain
Estrogens
Transcription Factors
Cell Proliferation
Ligands

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Endocrinology

Cite this

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title = "The NEDD8 pathway is required for proteasome-mediated degradation of human estrogen receptor (ER)-α and essential for the antiproliferative activity of ICI 182,780 in ERα-positive breast cancer cells",
abstract = "Steroid hormone receptors, including estrogen receptor-α (ERα), are ligand-activated transcription factors, and hormone binding leads to depletion of receptor levels via preteasome-mediated degradation. NEDD8 (neural precursor cell-expressed developmentally down-regulated) is an ubiquitin-like protein essential for protein processing and cell cycle progression. We recently demonstrated that ubiquitin-activating enzyme (Uba)3, the catalytic subunit of the NEDD8-activating enzyme, inhibits ERα transcriptional activity. Here we report that Uba3-mediated inhibition of ERα transactivation function is due to increased receptor protein turnover. Coexpression of Uba3 with ERα increased receptor degradation by the 26S proteasome. Inhibition of NEDD8 activation and conjugation diminished polyubiquitination of ERα and blocked proteasome-mediated degradation of receptor protein. The antiestrogen ICI 182,780 is known to induce ER degradation. In human MCF7 breast cancer cells modified to contain a disrupted NEDD8 pathway, ICI 182,780 degradation of ERα was impaired, and the antiestrogen was ineffective at inhibiting cell proliferation. This study provides the first evidence linking nuclear receptor degradation with the NEDD8 pathway and the ubiquitin-proteasome system, suggesting that the two pathways can act together to modulate ERα turnover and cellular responses to estrogens. Based on our observation that an intact NEDD8 pathway is essential for the antiproliferation activity of the ICI 182,780 in ERα positive breast cancer cells, we propose that disruptions in the NEDD8 pathway provide a mechanism by which breast cancer cells acquire antiestrogen resistance while retaining expression of ERα.",
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AU - Bigsby, Robert M.

AU - Nephew, Kenneth P.

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N2 - Steroid hormone receptors, including estrogen receptor-α (ERα), are ligand-activated transcription factors, and hormone binding leads to depletion of receptor levels via preteasome-mediated degradation. NEDD8 (neural precursor cell-expressed developmentally down-regulated) is an ubiquitin-like protein essential for protein processing and cell cycle progression. We recently demonstrated that ubiquitin-activating enzyme (Uba)3, the catalytic subunit of the NEDD8-activating enzyme, inhibits ERα transcriptional activity. Here we report that Uba3-mediated inhibition of ERα transactivation function is due to increased receptor protein turnover. Coexpression of Uba3 with ERα increased receptor degradation by the 26S proteasome. Inhibition of NEDD8 activation and conjugation diminished polyubiquitination of ERα and blocked proteasome-mediated degradation of receptor protein. The antiestrogen ICI 182,780 is known to induce ER degradation. In human MCF7 breast cancer cells modified to contain a disrupted NEDD8 pathway, ICI 182,780 degradation of ERα was impaired, and the antiestrogen was ineffective at inhibiting cell proliferation. This study provides the first evidence linking nuclear receptor degradation with the NEDD8 pathway and the ubiquitin-proteasome system, suggesting that the two pathways can act together to modulate ERα turnover and cellular responses to estrogens. Based on our observation that an intact NEDD8 pathway is essential for the antiproliferation activity of the ICI 182,780 in ERα positive breast cancer cells, we propose that disruptions in the NEDD8 pathway provide a mechanism by which breast cancer cells acquire antiestrogen resistance while retaining expression of ERα.

AB - Steroid hormone receptors, including estrogen receptor-α (ERα), are ligand-activated transcription factors, and hormone binding leads to depletion of receptor levels via preteasome-mediated degradation. NEDD8 (neural precursor cell-expressed developmentally down-regulated) is an ubiquitin-like protein essential for protein processing and cell cycle progression. We recently demonstrated that ubiquitin-activating enzyme (Uba)3, the catalytic subunit of the NEDD8-activating enzyme, inhibits ERα transcriptional activity. Here we report that Uba3-mediated inhibition of ERα transactivation function is due to increased receptor protein turnover. Coexpression of Uba3 with ERα increased receptor degradation by the 26S proteasome. Inhibition of NEDD8 activation and conjugation diminished polyubiquitination of ERα and blocked proteasome-mediated degradation of receptor protein. The antiestrogen ICI 182,780 is known to induce ER degradation. In human MCF7 breast cancer cells modified to contain a disrupted NEDD8 pathway, ICI 182,780 degradation of ERα was impaired, and the antiestrogen was ineffective at inhibiting cell proliferation. This study provides the first evidence linking nuclear receptor degradation with the NEDD8 pathway and the ubiquitin-proteasome system, suggesting that the two pathways can act together to modulate ERα turnover and cellular responses to estrogens. Based on our observation that an intact NEDD8 pathway is essential for the antiproliferation activity of the ICI 182,780 in ERα positive breast cancer cells, we propose that disruptions in the NEDD8 pathway provide a mechanism by which breast cancer cells acquire antiestrogen resistance while retaining expression of ERα.

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