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Nuclear receptors (NRs) regulate gene expression by binding specific DNA sequences consisting of AG[G/T]TCA or AGAACA half site motifs in a variety of configurations. However, those motifs/configurations alone do not adequately explain the diversity of NR function in vivo. Here, a systematic examination of DNA binding specificity by protein-binding microarrays (PBMs) of three closely related human NRs--HNF4α, retinoid X receptor alpha (RXRα) and COUPTF2--reveals an HNF4-specific binding motif (H4-SBM), xxxxCAAAGTCCA, as well as a previously unrecognized polarity in the classical DR1 motif (AGGTCAxAGGTCA) for HNF4α, RXRα and COUPTF2 homodimers. ChIP-seq data indicate that the H4-SBM is uniquely bound by HNF4α but not 10 other NRs in vivo, while NRs PXR, FXRα, Rev-Erbα appear to bind adjacent to H4-SBMs. HNF4-specific DNA recognition and transactivation are mediated by residues Asp69 and Arg76 in the DNA-binding domain; this combination of amino acids is unique to HNF4 among all human NRs. Expression profiling and ChIP data predict ≈ 100 new human HNF4α target genes with an H4-SBM site, including several Co-enzyme A-related genes and genes with links to disease. These results provide important new insights into NR DNA binding. 相似文献
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The N-terminal part of TIF1, a putative mediator of the ligand-dependent activation function (AF-2) of nuclear receptors, is fused to B-raf in the oncogenic protein T18. 总被引:35,自引:7,他引:35 下载免费PDF全文
B Le Douarin C Zechel J M Garnier Y Lutz L Tora P Pierrat D Heery H Gronemeyer P Chambon R Losson 《The EMBO journal》1995,14(9):2020-2033
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H-2RIIBP (RXR beta) heterodimerization provides a mechanism for combinatorial diversity in the regulation of retinoic acid and thyroid hormone responsive genes. 总被引:70,自引:10,他引:60 下载免费PDF全文
M S Marks P L Hallenbeck T Nagata J H Segars E Appella V M Nikodem K Ozato 《The EMBO journal》1992,11(4):1419-1435
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Ribeiro RC Feng W Wagner RL Costa CH Pereira AC Apriletti JW Fletterick RJ Baxter JD 《The Journal of biological chemistry》2001,276(18):14987-14995
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COUP orphan receptors are negative regulators of retinoic acid response pathways. 总被引:13,自引:11,他引:13 下载免费PDF全文
P Tran X K Zhang G Salbert T Hermann J M Lehmann M Pfahl 《Molecular and cellular biology》1992,12(10):4666-4676
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Nuclear receptors (NRs) associate with various coactivator proteins via direct interaction with a short LXXLL motif (also
called NR box) that is present among coactivators. Here we identified the critical residues within or outside NR box-2 or
-3 of SRC-1, which are required for the optimal interaction with LXR/RXR heterodimers using the yeast one- plus two-hybrid
screening system. The critical residues of NR box-2 were broadly located from position −4 to +5 of the NR box (where +1 is
the first L of LXXLL motif), whereas those of NR box-3 were located between −1 and +5. We assessed the functional and physical
interactions between the isolated NR box-2 mutants and various NRs. Among the NR box-2 mutants, H-3Q, I-1T/V and H+2P mutants
evidenced different interaction profiles depending on the target NRs, thereby indicating that these residues are the specific
determinants required for the selective interaction between the SRC-1 NR box-2 and a given receptor. 相似文献
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