Tamoxifen-bound estrogen receptor (ER) strongly interacts with the nuclear matrix protein HET/SAF-B, a novel inhibitor of ER-mediated transactivation.
The estrogen receptor (ER) is a ligand-dependent transcription factor that acts in a cell- and promoter-specific manner. Evidence suggests that the activity of the ER can be regulated by a number of other stimuli (e.g. growth factors) and that the effects of the ER are modulated by nuclear factors termed coregulators. While the interplay among these factors may in part explain the pleiotropic effects elicited by the ER, there are several other less well described mechanisms of control, such as interactions with the nuclear matrix. Here we report that the nuclear matrix protein/scaffold attachment factor HET/SAF-B is an ER-interacting protein. ER and HET/SAF-B interact in in vitro binding assays, with HET binding to both the ER DNA-binding domain and the hinge region. Coimmunoprecipitation experiments reveal that HET/SAF-B and ER associate in cell lines in the presence or absence of estradiol, but binding is increased by the antiestrogen tamoxifen. HET/SAF-B enhances tamoxifen antagonism of estrogen-induced ER-mediated transactivation, but at high concentrations can inhibit both estrogen and tamoxifen-induced ER activity. HET/SAF-B-mediated repression of ER activity is dependent upon interaction with the ER-DBD. While the existence of high-affinity binding sites for the ER in the nuclear matrix has been known for some time, we now provide evidence of a specific nuclear matrix protein binding to the ER. Furthermore, our data showing that HET/SAF-B binds to ER particularly strongly in the presence of tamoxifen suggests that it may be important for the antagonist effect of tamoxifen.
Oesterreich
S
S
Department of Medicine, University of Texas Health Science Center, San Antonio 78284, USA. steffio@bcm.tmc.edu
Zhang
Q
Q
Hopp
T
T
Fuqua
S A
SA
Michaelis
M
M
Zhao
H H
HH
Davie
J R
JR
Osborne
C K
CK
Lee
A V
AV
D000230:Adenocarcinoma / Q000378:metabolism / Q000473:pathology; D000818:Animals; D001483:Base Sequence; D001859:Bone Neoplasms / Q000473:pathology; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology; D019556:COS Cells; D006528:Carcinoma, Hepatocellular / Q000473:pathology; D002522:Chlorocebus aethiops; D004247:DNA / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism*; D003864:Depression, Chemical; D004958:Estradiol / Q000494:pharmacology; D020847:Estrogen Receptor Modulators / Q000378:metabolism / Q000494:pharmacology*; D005260:Female; D006801:Humans; D008113:Liver Neoplasms / Q000473:pathology; D046911:Macromolecular Substances; D036961:Matrix Attachment Region Binding Proteins; D008969:Molecular Sequence Data; D009363:Neoplasm Proteins / Q000378:metabolism; D009376:Neoplasms, Hormone-Dependent / Q000378:metabolism / Q000473:pathology; D034521:Nuclear Matrix-Associated Proteins; D009687:Nuclear Proteins / Q000378:metabolism*; D012516:Osteosarcoma / Q000473:pathology; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D011960:Receptors, Estrogen / Q000187:drug effects / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D013329:Structure-Activity Relationship; D013629:Tamoxifen / Q000378:metabolism / Q000494:pharmacology*; D015533:Transcriptional Activation / Q000187:drug effects*; D014407:Tumor Cells, Cultured / Q000187:drug effects
D004268:DNA-Binding Proteins; D020847:Estrogen Receptor Modulators; D046911:Macromolecular Substances; D036961:Matrix Attachment Region Binding Proteins; D009363:Neoplasm Proteins; D034521:Nuclear Matrix-Associated Proteins; D009687:Nuclear Proteins; D011960:Receptors, Estrogen; D011993:Recombinant Fusion Proteins; C109132:SAFB protein, human; D013629:Tamoxifen; D004958:Estradiol; D004247:DNA