Saatcioglu F, Bartunek P, Deng T, Zenke M, Karin M
Department of Pharmacology, School of Medicine, University of California, San Diego, La Jolla 92093-0636.
Mol Cell Biol. 1993 Jun;13(6):3675-85. doi: 10.1128/mcb.13.6.3675-3685.1993.
The thyroid hormone (T3) receptor type alpha, the c-ErbA alpha proto-oncoprotein, stimulates transcription of T3-dependent promoters, interferes with AP-1 activity, and induces erythroid differentiation in a ligand-dependent manner. The v-ErbA oncoprotein does not bind hormone and has lost all of these activities. Using c-ErbA/v-ErbA chimeras, we found that a deletion of 9 amino acids, conserved among many members of the nuclear receptor superfamily, which are located at the extreme carboxy terminus of c-ErbA alpha is responsible for loss of both transactivation and transcriptional interference activities. Single, double, and triple amino acid substitutions within this region completely abolished T3-dependent transcriptional activation, interference with AP-1 activity, and decreased T3 binding by c-ErbA alpha. However, the lower T3 binding by these mutants does not fully account for the loss of transactivation and transcriptional interference, since a c-ErbA/v-ErbA chimera which was similarly reduced in T3 binding activity has retained both of these functions. Deletion of homologous residues in the retinoic acid receptor alpha (RAR alpha) resulted in a similar loss of transactivation and transcriptional interference activities. The ability of c-ErbA alpha to induce differentiation of transformed erythroblasts is also impaired by all of the mutations introduced into the conserved carboxy-terminal sequence. We conclude that this 9-amino-acid conserved region is essential for normal biological function of c-ErbA alpha and RAR alpha and possibly other T3 and RA receptors.
甲状腺激素（T3）α型受体，即c-ErbAα原癌蛋白，可刺激T3依赖性启动子的转录，干扰AP-1活性，并以配体依赖性方式诱导红细胞分化。v-ErbA癌蛋白不结合激素，且已丧失所有这些活性。利用c-ErbA/v-ErbA嵌合体，我们发现位于c-ErbAα极端羧基末端的一段9个氨基酸的缺失，该缺失在核受体超家族的许多成员中保守，是导致反式激活和转录干扰活性丧失的原因。该区域内的单个、双个和三个氨基酸取代完全消除了T3依赖性转录激活、对AP-1活性的干扰，并降低了c-ErbAα与T3的结合。然而，这些突变体与T3较低的结合并不能完全解释反式激活和转录干扰的丧失，因为一个T3结合活性同样降低的c-ErbA/v-ErbA嵌合体保留了这两种功能。视黄酸受体α（RARα）中同源残基的缺失导致了类似的反式激活和转录干扰活性丧失。引入保守羧基末端序列的所有突变也损害了c-ErbAα诱导转化成红细胞分化的能力。我们得出结论，这个9个氨基酸的保守区域对于c-ErbAα和RARα以及可能其他T3和视黄酸受体的正常生物学功能至关重要。
