Molecular mechanisms of selective estrogen receptor modulator (SERM) action.
Molecular mechanisms of selective estrogen receptor modulator (SERM) action.
复制标题
DOI：
--
复制
发表时间：
2000-11
期刊：
影响因子：
--
通讯作者：
M. Dutertre;Carolyn L. Smith
中科院分区：
文献类型：
--
作者：
M. Dutertre;Carolyn L. Smith
在女性中，雌激素在生殖中起着关键作用，对骨骼、心血管和中枢神经系统有有益的影响。大多数雌激素反应由雌激素受体（ER）（ER α或ER β）介导，其是配体依赖性转录因子的核受体超家族的成员。选择性雌激素受体调节剂（SERM）是ER配体，在某些组织中起雌激素样作用，但在其他组织中阻断雌激素作用。因此，SERM可能表现出激动或拮抗的生物特性，这取决于检查其活性的背景。例如，SERM他莫昔芬和雷洛昔芬都在乳腺中表现出ER拮抗剂活性，在骨中表现出激动剂活性，但只有他莫昔芬在子宫中表现出激动剂活性。许多研究已经检查了SERM选择性的分子基础。总的来说，它们表明不同的ER配体诱导受体中不同的结构变化，影响其与其他蛋白质相互作用的能力（例如，辅激活子或辅阻遏子），其对于调节靶基因转录至关重要。辅激活子和辅阻遏子的相对表达，以及ER及其靶基因启动子的性质影响SERM的生物学特性。总的来说，SERM选择性反映了ER形式和辅助调节因子的多样性，其表达的细胞类型差异以及ER靶基因的多样性。该模型为理解SERM作用的分子机制提供了基础，并有助于识别具有增强的组织或靶基因选择性的新SERM。
In females, estrogens play a key role in reproduction and have beneficial effects on the skeletal, cardiovascular, and central nervous systems. Most estrogenic responses are mediated by estrogen receptors (ERs), either ER alpha or ER beta, which are members of the nuclear receptor superfamily of ligand-dependent transcription factors. Selective estrogen receptor modulators (SERMs) are ER ligands that in some tissues act like estrogens, but block estrogen action in others. Thus, SERMs may exhibit an agonistic or antagonistic biocharacter depending on the context in which their activity is examined. For example, the SERMs tamoxifen and raloxifene both exhibit ER antagonist activity in breast and agonist activity in bone, but only tamoxifen manifests agonist activity in the uterus. Numerous studies have examined the molecular basis for SERM selectivity. Collectively they indicate that different ER ligands induce distinct structural changes in the receptor that influence its ability to interact with other proteins (e.g., coactivators or corepressors) critical for the regulation of target gene transcription. The relative expression of coactivators and corepressors, and the nature of the ER and of its target gene promoter affect SERM biocharacter. Taken together, SERM selectivity reflects the diversity of ER forms and coregulators, cell type differences in their expression, and the diversity of ER target genes. This model provides a basis for understanding the molecular mechanisms of SERM action, and should help identify new SERMs with enhanced tissue or target gene selectivity.