共查询到20条相似文献,搜索用时 31 毫秒
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A Takeshita PM Yen M Ikeda GR Cardona Y Liu N Koibuchi ER Norwitz WW Chin 《Canadian Metallurgical Quarterly》1998,273(34):21554-21562
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Lack of coactivator interaction can be a mechanism for dominant negative activity by mutant thyroid hormone receptors 总被引:1,自引:0,他引:1
We studied the interactions of two natural thyroid hormone receptor (TR) mutants from patients with resistance to thyroid hormone (RTH) and an artificial TR mutant with a nuclear receptor corepressor, N-CoR, and a steroid receptor coactivator, SRC-1. In electrophoretic mobility shift assays, wild-type TRbeta-1 interacted with N-CoR in the absence of ligand, whereas T3 caused dissociation of the TRbeta-1/N-CoR complex and formation of TRbeta-1/SRC-1 complex. In contrast, a natural mutant (G345R) with poor T3-binding affinity formed TRbeta-1/N-CoR complex, both in the absence and presence of T3, but could not form TRbeta-1/SRC-1 complex. Another TR mutant, which bound T3 with normal affinity and containing a mutation in the AF-2 region (E457D), had normal interactions with N-CoR but could not bind SRC-1. Both these mutants had strong dominant negative activity on wild-type TR transactivation. Studies with a TR mutant that had slightly decreased T3-binding affinity (R320H) showed a T3-dependent decrease in binding to N-CoR and increase in binding to SRC-1 that reflected its decreased ligand binding affinity. Additionally, when N-CoR and SRC-1 were added to these receptors at various T3 concentrations in electrophoretic mobility shift assays, TR/N-CoR and TR/SRC-1 complexes, but not intermediate complexes were observed, suggesting that N-CoR release is necessary before SRC-1 binding to TR. Our data provide new insight on the molecular mechanisms of dominant negative activity in RTH and suggest that the inability of mutant TRs to interact with coactivators such as SRC-1, which results from reduced T3-binding affinity, is a determinant of dominant negative activity. 相似文献
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Functional analysis of a transactivation domain in the thyroid hormone beta receptor 总被引:1,自引:0,他引:1
Y Tone TN Collingwood M Adams VK Chatterjee 《Canadian Metallurgical Quarterly》1994,269(49):31157-31161
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CA Berrevoets P Doesburg K Steketee J Trapman AO Brinkmann 《Canadian Metallurgical Quarterly》1998,12(8):1172-1183
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S Nakajima 《Canadian Metallurgical Quarterly》1998,56(7):1717-1721
The 1,25-dihydroxyvitamin D receptor (VDR) belongs to the nuclear hormone receptor family. Mutational analysis revealed that the carboxyl-terminal region between leucine-417 and glutamic acid-420 of the human VDR is essential for the ligand-dependent transactivation. Mutant VDR at this AF-2 region exhibits only weak suppressive effect on the transactivation via the wild type receptor compared to the estrogen and vitamin A receptors, which confer the strong dominant negative effect. Using the AF-2 mutant VDR protein, we demonstrated a 65kD nuclear protein, which binds to the AF-2 region of the human VDR in a ligand dependent manner. 相似文献
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W Feng RC Ribeiro RL Wagner H Nguyen JW Apriletti RJ Fletterick JD Baxter PJ Kushner BL West 《Canadian Metallurgical Quarterly》1998,280(5370):1747-1749
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