TY - JOUR
T1 - Solution structure and antiestrogenic activity of the unique C-terminal, NR-box motif-containing region of MTA1s
AU - Singh, Rajesh R.
AU - Kaluarachchi, Kumaralal
AU - Chen, Mingzhi
AU - Rayala, Suresh K.
AU - Balasenthil, Seetharaman
AU - Ma, Jianpeng
AU - Kumar, Rakesh
PY - 2006/9/1
Y1 - 2006/9/1
N2 - Metastasis tumor-associated 1 short form (MTA1s) is a naturally occurring, alternatively spliced variant of MTA1 that functions as a repressor of estrogen receptor (ER) α transcriptional functions, at least in part by binding and sequestering ER α in the cytoplasm. A unique C-terminal 33-amino acid region containing a nuclear receptor (NR)-box motif (-LRILL-) mediates binding of MTA1s with ERα and is indispensable in this interaction. Here, we elucidated the solution structure of this 33-amino acid region by NMR spectroscopy. We found a predominance of the α-helical region toward the N-terminal region, which includes the NR-box motif. In silico docking and comparison studies showed similarities between the NR-box motif of MTA1s and a similar motif of coregulators, both in structure and mode of ERα binding. In MCF-7 breast cancer cells, the MTA1s peptide effectively repressed ERα transactivation function, as evidenced by the estrogen response element-luc assay and down-regulation of estrogen-induced genes. In mechanistic studies, we found that the antiestrogenic effects of the MTA1s peptide were due to its ability to compete with the coactivator recruitment to ERα. Furthermore, the peptide efficiently repressed estrogen-induced proliferation and anchorage-independent growth of MCF-7 cells. In addition, the MTA1s peptide blocked the progression of tumors formed by MCF-7 cells overexpressing an ERα coactivator in a xenograft-based assay. In brief, the characterization of structure and antiestrogenic activity of MTA1s peptide highlight its therapeutic potential.
AB - Metastasis tumor-associated 1 short form (MTA1s) is a naturally occurring, alternatively spliced variant of MTA1 that functions as a repressor of estrogen receptor (ER) α transcriptional functions, at least in part by binding and sequestering ER α in the cytoplasm. A unique C-terminal 33-amino acid region containing a nuclear receptor (NR)-box motif (-LRILL-) mediates binding of MTA1s with ERα and is indispensable in this interaction. Here, we elucidated the solution structure of this 33-amino acid region by NMR spectroscopy. We found a predominance of the α-helical region toward the N-terminal region, which includes the NR-box motif. In silico docking and comparison studies showed similarities between the NR-box motif of MTA1s and a similar motif of coregulators, both in structure and mode of ERα binding. In MCF-7 breast cancer cells, the MTA1s peptide effectively repressed ERα transactivation function, as evidenced by the estrogen response element-luc assay and down-regulation of estrogen-induced genes. In mechanistic studies, we found that the antiestrogenic effects of the MTA1s peptide were due to its ability to compete with the coactivator recruitment to ERα. Furthermore, the peptide efficiently repressed estrogen-induced proliferation and anchorage-independent growth of MCF-7 cells. In addition, the MTA1s peptide blocked the progression of tumors formed by MCF-7 cells overexpressing an ERα coactivator in a xenograft-based assay. In brief, the characterization of structure and antiestrogenic activity of MTA1s peptide highlight its therapeutic potential.
UR - http://www.scopus.com/inward/record.url?scp=33748743548&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=33748743548&partnerID=8YFLogxK
U2 - 10.1074/jbc.M604444200
DO - 10.1074/jbc.M604444200
M3 - Article
C2 - 16807247
AN - SCOPUS:33748743548
SN - 0021-9258
VL - 281
SP - 25612
EP - 25621
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 35
ER -