Proteasome-mediated mineralocorticoid receptor degradation attenuates transcriptional response to aldosterone

Kenichi Yokota, Hirotaka Shibata, Sakiko Kobayashi, Noriko Suda, Ayano Murai, Isao Kurihara, Ikuo Saito, Takao Saruta

Research output: Contribution to journalArticle

21 Citations (Scopus)

Abstract

The ubiquitin-proteasome pathway regulates the turnover of many nuclear hormone receptors, such as the estrogen receptor. For estrogen receptor, proteasome inhibition decreases ligand-mediated transcription. We provide evidence that the mineralocorticoid receptor (MR) is degraded by the ubiquitin-proteasome pathway in a ligand-dependent manner and that proteasomal inhibition results in increased accumulation of the MR with enhancement of transcriptional response to aldosterone. Examination of the primary sequence of human and rat MR has identified two candidate PEST degradation motifs. Mutation of lysine 715 and/or 367 within this PEST element failed to prevent degradation of MR protein or transcriptional activity mediated by aldosterone, indicating that other lysine residues are targeted by proteasomal degradation of MR. These findings demonstrate a coupling between MR up-regulation and transcriptional hyperactivity.

Original languageEnglish
Pages (from-to)611-616
Number of pages6
JournalEndocrine Research
Volume30
Issue number4
DOIs
Publication statusPublished - 2004 Dec 1

Keywords

  • Aldosterone
  • Mineralcorticoid receptor
  • Proteasome
  • Ubiquitin

ASJC Scopus subject areas

  • Endocrinology

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