Ligand-dependent corepressor LCoR is an attenuator of progesterone-regulated gene expression.
Ligand-dependent corepressor LCoR interacts with the progesterone receptor (PR) and estrogen receptor ERalpha in the presence of hormone. LCoR contains tandem N-terminal PXDLS motifs that recruit C-terminal-binding protein (CtBP) corepressors as well as a C-terminal helix-turn-helix (HTH) domain. Here, we analyzed the function of these domains in coregulation of PR- and ERalpha-regulated gene expression. LCoR and CtBP1 colocalize in nuclear bodies that also contain CtBP-interacting protein CtIP and polycomb group repressor complex marker BMI1. Coexpression of CtBP1 in MCF7 or T47D breast cancer cells augmented corepression by LCoR, whereas coexpression of CtIP did not, consistent with direct interaction of LCoR with CtBP1, but not CtIP. The N-terminal region containing the PXDLS motifs is necessary and sufficient for CTBP1 recruitment and essential for full corepression. However, LCoR function was also strongly dependent on the helix-turn-helix domain, as its deletion completely abolished corepression. LCoR, CtBP, and CtIP were recruited to endogenous PR- and ERalpha-stimulated genes in a hormone-dependent manner. Similarly, LCoR was recruited to estrogen-repressed genes, whereas hormone treatment reduced CtBP1 binding. Small interfering RNA-mediated knockdown of LCoR or CtBP1 augmented expression of progesterone- and estrogen-stimulated reporter genes as well as endogenous progesterone-stimulated target genes. In contrast, their ablation had gene-specific effects on ERalpha-regulated transcription that generally led to reduced gene expression. Taken together, these results show that multiple domains contribute to LCoR function. They also reveal a role for LCoR and CtBP1 as attenuators of progesterone-regulated transcription but suggest that LCoR and CtBP1 can act to enhance transcription of some genes.
Palijan
Ana
A
Department of Physiology, McGill University, Montreal, Quebec H3G 1Y6, Canada.
Fernandes
Isabelle
I
Verway
Mark
M
Kourelis
Maria
M
Bastien
Yolande
Y
Tavera-Mendoza
Luz E
LE
Sacheli
Aaron
A
Bourdeau
Veronique
V
Mader
Sylvie
S
White
John H
JH
D000429:Alcohol Oxidoreductases / Q000378:metabolism; D002352:Carrier Proteins / Q000378:metabolism; D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins / Q000378:metabolism; D004706:Endodeoxyribonucleases; D047628:Estrogen Receptor alpha / Q000502:physiology; D005786:Gene Expression Regulation; D006801:Humans; D009687:Nuclear Proteins / Q000378:metabolism; D011374:Progesterone / Q000502:physiology*; D012097:Repressor Proteins / Q000502:physiology*; D014158:Transcription, Genetic
D002352:Carrier Proteins; D004268:DNA-Binding Proteins; D047628:Estrogen Receptor alpha; C472166:LCOR protein, human; D009687:Nuclear Proteins; D012097:Repressor Proteins; D011374:Progesterone; D000429:Alcohol Oxidoreductases; C096794:C-terminal binding protein; D004706:Endodeoxyribonucleases; C410741:RBBP8 protein, human