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Articles by A Matsushima
Total Records ( 2 ) for A Matsushima
  Y Takeda , X Liu , M Sumiyoshi , A Matsushima , M Shimohigashi and Y. Shimohigashi
 

Estrogen-related receptor (ERR), one of the 48 human nuclear receptors, has a fully active conformation with no ligand. We recently demonstrated that ERR binds strongly bisphenol A (BPA), one of the nastiest endocrine disruptors, and thus retaining ERR's high basal constitutive activity. A report that BPA accumulates in the human maternal–fetal placental unit has led us to hypothesize that a large amount of ERR might exist in the human placenta. Here we report evidence that placenta indeed expresses ERR exceptionally strongly. We first ascertained the presence of nine different ERR mRNA variants and the resulting three ERR protein isoforms. By real-time PCR, we estimated the relative amount of ERR mRNA using total RNA extracts from human reproductive tissues. Placenta was found to express ERR extremely highly. Among the three ERR protein isoforms, placenta exclusively expresses the type-1 isoform, which possesses additional 23-mer amino-acid residues at the N-terminus of the ordinary ERR. This N-terminal elongation was found to elevate by approximately 50% the basal constitutive activity of ERR, as evidenced in the luciferase reporter gene assay. The present results suggest that BPA accumulates in the placenta by binding to ERR.

  X Liu , A Matsushima , H Okada and Y. Shimohigashi
 

Bisphenol A (BPA) strongly binds to human estrogen-related receptor (ERR). BPA is an oestrogenic endocrine disruptor that influences various physiological functions at very low doses. BPA functions as an inverse-type antagonist of ERR to retain its high basal constitutive activity by inhibiting the deactivating inverse agonist activity of 4-hydroxytamoxifen (4-OHT). We recently demonstrated that ERR receptor residues Glu275 and Arg316 function as the intrinsic binding site of BPA’s phenol-hydroxyl group. We also determined the chief importance of phenol-hydroxylArg316 hydrogen bonding and the corroborative role of phenol-hydroxylGlu275 hydrogen bonding. However, there appeared to be a distinct difference between the receptor binding modes of BPA and 4-OHT. In the present study, using tritium-labelled or non-labelled BPA and 4-OHT, we evaluated in detail the receptor binding capabilities of wild-type ERR and its mutants with amino acid alterations at positions 275 and 316. Both compounds exhibited a strong binding ability to wild-type ERR due to the hydrogen bonding to Glu275 and Arg316. However, 4-OHT revealed significantly reduced occupancy for both wild-type and mutant receptors. The data obtained suggest that 4-OHT barely binds to ERR due to the strong ability of Glu275 and Arg316 to recruit phenol compounds.

 
 
 
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