Mahfoudi A, Roulet E, Dauvois S, Parker M G, Wahli W
Institut de Biologie Animale, Université de Lausanne, Switzerland.
Proc Natl Acad Sci U S A. 1995 May 9;92(10):4206-10. doi: 10.1073/pnas.92.10.4206.
The estrogen receptor (ER) stimulates transcription of target genes by means of its two transcriptional activation domains, AF-1 in the N-terminal part of the receptor and AF-2 in its ligand-binding domain. AF-2 activity is dependent upon a putative amphipathic alpha-helix between residues 538 and 552 in the mouse ER. Point mutagenesis of conserved hydrophobic residues within this region reduces estrogen-dependent transcriptional activation without affecting hormone and DNA binding significantly. Here we show that these mutations dramatically alter the pharmacology of estrogen antagonists. Both tamoxifen and ICI 164,384 behave as strong agonists in HeLa cells expressing the ER mutants. In contrast to the wild-type ER, the mutant receptors maintain nuclear localization and DNA-binding activity after ICI 164,384 treatment. Structural alterations in AF-2 caused by gene mutations such as those described herein or by estrogen-independent signaling pathways may account for the insensitivity of some breast cancers to tamoxifen treatment.
雌激素受体（ER）通过其两个转录激活结构域刺激靶基因转录，这两个结构域分别是位于受体N端的AF-1和位于其配体结合结构域的AF-2。AF-2的活性依赖于小鼠ER中538至552位残基之间假定的两亲性α螺旋。该区域内保守疏水残基的点突变会降低雌激素依赖性转录激活，而对激素和DNA结合影响不大。在此我们表明，这些突变显著改变了雌激素拮抗剂的药理学特性。在表达ER突变体的HeLa细胞中，他莫昔芬和ICI 164,384均表现为强效激动剂。与野生型ER不同，ICI 164,384处理后，突变体受体保持核定位和DNA结合活性。由本文所述的基因突变或雌激素非依赖性信号通路引起的AF-2结构改变，可能是某些乳腺癌对他莫昔芬治疗不敏感的原因。
