Turning off estrogen receptor beta-mediated transcription requires estrogen-dependent receptor proteolysis.
Recent studies have shed light on the ligand-dependent transactivation mechanisms of nuclear receptors (NRs). When the ligand dose is reduced, the transcriptional activity of NRs should be downregulated. Here we show that a ubiquitin-proteasome pathway plays a key role in turning off transcription mediated by estrogen receptor beta (ERbeta). ERbeta shows estrogen-dependent proteolysis, and its degradation is regulated by two regions in the receptor. The N-terminal 37-amino acid-region is necessary for the recruitment of the ubiquitin ligase, i.e., the carboxyl terminus of HSC70-interacting protein (CHIP), to degrade ERbeta. In contrast, the C-terminal F domain protects ligand-unbound ERbeta from proteolysis to abrogate proteasome association. Suppression of CHIP by interfering RNA inhibited this switching off of receptor-mediated transcription when the ligand dose was reduced. Our results suggest that after ligand withdrawal, the active form of the NR is selectively eliminated via ligand-dependent proteolysis to downregulate receptor-mediated transcription.
Tateishi
Yukiyo
Y
Graduate School of Life and Environmental Sciences, University of Tsukuba, Ibaraki 305-8572, Japan.
Sonoo
Raku
R
Sekiya
Yu-ichi
Y
Sunahara
Nanae
N
Kawano
Miwako
M
Wayama
Mitsutoshi
M
Hirota
Ryuichi
R
Kawabe
Yoh-ichi
Y
Murayama
Akiko
A
Kato
Shigeaki
S
Kimura
Keiji
K
Yanagisawa
Junn
J
D000818:Animals; D002460:Cell Line; D047629:Estrogen Receptor beta / Q000235:genetics / Q000378:metabolism*; D004967:Estrogens / Q000378:metabolism*; D005786:Gene Expression Regulation; D006801:Humans; D008024:Ligands; D051379:Mice; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D017434:Protein Structure, Tertiary; D034622:RNA Interference; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism
D047629:Estrogen Receptor beta; D004967:Estrogens; D008024:Ligands; D011993:Recombinant Fusion Proteins; C467728:STUB1 protein, human; D044767:Ubiquitin-Protein Ligases; D046988:Proteasome Endopeptidase Complex