Estrogen receptor variants ERdelta5 and ERdelta7 down-regulate wild-type estrogen receptor activity.
Estrogen receptor variants ERdelta5 and ERdelta7 down-regulate wild-type estrogen receptor activity.
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雌激素受体变体 ERdelta5 和 ERdelta7 下调野生型雌激素受体活性。
DOI：
10.1016/s0303-7207(99)00125-2
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发表时间：
1999
影响因子：
4.1
通讯作者：
Khan,SA
中科院分区：
文献类型：
--
作者：
Wang,H;Zeng,X;Khan,SA
雌激素受体（ER）在调节雌激素的作用中起着关键作用。它是包括乳腺癌在内的许多疾病的内分泌治疗的主要目标。ER包含六个与不同功能相关的结构域；所有六个结构域的存在是配体依赖性受体活性所必需的。据报道，在乳腺肿瘤和其他肿瘤中，ER变异通常缺乏一个或多个结构域或一个结构域的一部分。这种缺失会对内质网活性、细胞对激素的反应以及对激素治疗的反应产生巨大影响。我们使用简单和快速酵母系统来更清楚地了解ER变异体如何改变野生型ER （wtER）对雌激素和抗雌激素的反应。我们在含有ERE-LacZ报告基因的酵母中，与水共表达ER变异体ERΔ5或ERΔ7。我们发现ERΔ5和ERΔ7对1 nM 17β-雌二醇的反应分别降低了41 - 43%和24-34%。单独，ERΔ5表现出弱的激素独立转录活性，不受他莫昔芬或ICI 182780的影响。反之，ERΔ7则没有构象活性，对配体没有反应。为了进一步了解ERΔ5和ERΔ7是否通过形成一种不同的wtER异源二聚体来影响wtER活性，我们使用酵母双杂交系统。蛋白互作结果表明，ERΔ5和ERΔ7既不能与自身形成同型二聚体，也不能与水分子形成异源二聚体。这一发现表明ERΔ5和ERΔ7对wtER的影响不是通过异源二聚化抑制wtER介导的。
The estrogen receptor (ER) plays a key role in mediating the effect of estrogens. It is the primary target for endocrine therapy for many diseases, including breast cancer. The ER contains six domains that are associated with distinct functions; the presence of all six domains is required for ligand-dependent receptor activity. ER variants, reported in breast tumors and other neoplasms, usually lack one or more domains or a part of a domain. Such deletions can have dramatic effects on ER activity, cellular response to hormone, and response to hormonal therapy. We used simple and rapid yeast systems to understand more clearly how ER variants alter the response of wild-type ER (wtER) to estrogen and antiestrogens. We co-expressed ER variant, ERΔ5 or ERΔ7, with wtER in yeast containing an ERE-LacZ reporter. We found that ERΔ5 and ERΔ7 decreased the response of wtER to 1 nM 17β-estradiol by 41–43 and 24–34%, respectively. Alone, ERΔ5 displayed weak hormone-independent transcriptional activity that was not affected by tamoxifen or ICI 182,780. ERΔ7, in contrast, showed no constitutive activity and no response to ligands. To further understand whether ERΔ5 and ERΔ7 affect wtER activity by forming a variant:wtER heterodimer, we used the yeast two-hybrid system. The protein–protein interaction results showed that ERΔ5 and ERΔ7 could form neither homodimers with themselves nor heterodimers with wtER. This finding suggests that the influence of ERΔ5 and ERΔ7 on wtER is not mediated by suppressing wtER through heterodimerization.