Proteasome-dependent degradation of the human estrogen receptor

Zafar Nawaz, David M. Lonard, Andrew P. Dennis, Carolyn L. Smith, Bert W. O'Malley

Research output: Contribution to journalArticle

457 Citations (Scopus)

Abstract

In eukaryotic cells, the ubiquitin-proteasome pathway is the major mechanism for the targeted degradation of proteins with short half-lives. The covalent attachment of ubiquitin to lysine residues of targeted proteins is a signal for the recognition and rapid degradation by the proteasome, a large multi-subunit protease. In this report, we demonstrate that the human estrogen receptor (ER) protein is rapidly degraded in mammalian cells in an estradiol-dependent manner. The treatment of mammalian cells with the proteasome inhibitor MG132 inhibits activity of the proteasome and blocks ER degradation, suggesting that ER protein is turned over through the ubiquitin- proteasome pathway. In addition, we show that in vitro ER degradation depends on ubiquitin-activating E1 enzyme (UBA) and ubiquitin-conjugating E2 enzymes (UBCs), and the proteasome inhibitors MG132 and lactacystin block ER protein degradation in vitro. Furthermore, the UBA/UBCs and proteasome inhibitors promote the accumulation of higher molecular weight forms of ER. The UBA and UBCs, which promote ER degradation in vitro, have no significant effect on human progesterone receptor and human thyroid hormone receptor β proteins.

Original languageEnglish
Pages (from-to)1858-1862
Number of pages5
JournalProceedings of the National Academy of Sciences of the United States of America
Volume96
Issue number5
DOIs
StatePublished - Mar 2 1999
Externally publishedYes

Fingerprint

Proteasome Endopeptidase Complex
Estrogen Receptors
Proteasome Inhibitors
Ubiquitin
Proteolysis
Ubiquitin-Activating Enzymes
Ubiquitin-Conjugating Enzymes
Thyroid Hormone Receptors
Eukaryotic Cells
Progesterone Receptors
Lysine
Estradiol
Proteins
Peptide Hydrolases
Molecular Weight
In Vitro Techniques
estrophilin
benzyloxycarbonylleucyl-leucyl-leucine aldehyde

ASJC Scopus subject areas

  • Genetics
  • General

Cite this

Proteasome-dependent degradation of the human estrogen receptor. / Nawaz, Zafar; Lonard, David M.; Dennis, Andrew P.; Smith, Carolyn L.; O'Malley, Bert W.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 96, No. 5, 02.03.1999, p. 1858-1862.

Research output: Contribution to journalArticle

Nawaz, Zafar ; Lonard, David M. ; Dennis, Andrew P. ; Smith, Carolyn L. ; O'Malley, Bert W. / Proteasome-dependent degradation of the human estrogen receptor. In: Proceedings of the National Academy of Sciences of the United States of America. 1999 ; Vol. 96, No. 5. pp. 1858-1862.
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