Dedhar S, Rennie P S, Shago M, Hagesteijn C Y, Yang H, Filmus J, Hawley R G, Bruchovsky N, Cheng H, Matusik R J
Division of Cancer Research, University of Toronto, Ontario, Canada.
Nature. 1994 Feb 3;367(6462):480-3. doi: 10.1038/367480a0.
We have shown that a polypeptide of M(r) 60,000 (60K) that shares N-terminal homology with a calcium-binding protein, calreticulin, can bind to an amino-acid sequence motif, KXGFFKR, found in the cytoplasmic domains of all integrin alpha-subunits. The homologous amino-acid sequence, KXFFKR (where X is either G, A or V), is also present in the DNA-binding domain of all known members of the steroid hormone receptor family; amino acids in this sequence make direct contact with nucleotides in their DNA-responsive elements and are crucial for DNA binding. Here we show that both the 60K protein (p60), purified on a KLGFFKR-Sepharose affinity matrix, and recombinant calreticulin can inhibit the binding of androgen receptor to its hormone-responsive DNA element in a KXFFKR-sequence-specific manner. Calreticulin can also inhibit androgen receptor and retinoic acid receptor transcriptional activities in vivo, as well as retinoic acid-induced neuronal differentiation. Our results indicate that calreticulin can act as an important modulator of the regulation of gene transcription by nuclear hormone receptors.
我们已经证明，一种分子量为60,000（60K）的多肽，其与钙结合蛋白钙网蛋白具有N端同源性，能够结合到在所有整联蛋白α亚基的胞质结构域中发现的氨基酸序列基序KXGFFKR上。同源氨基酸序列KXFFKR（其中X为G、A或V）也存在于类固醇激素受体家族所有已知成员的DNA结合结构域中；该序列中的氨基酸与它们的DNA反应元件中的核苷酸直接接触，并且对于DNA结合至关重要。在此我们表明，在KLGFFKR - 琼脂糖亲和基质上纯化的60K蛋白（p60）和重组钙网蛋白都能以KXFFKR序列特异性的方式抑制雄激素受体与其激素反应性DNA元件的结合。钙网蛋白在体内还能抑制雄激素受体和视黄酸受体的转录活性，以及视黄酸诱导的神经元分化。我们的结果表明，钙网蛋白可作为核激素受体调节基因转录的重要调节剂。
