野生类型的激活和构成性活性的雌激素受体α的激活
John B Psaltis1, Qiaochu Wang2, Gai Yan1
1Department of Oncology, Georgetown University, Washington, DC, United States.
Frontiers in endocrinology
|August 26, 2024
概括
激活雌激素受体α (ERα),类似于,并加剧乳腺癌中常见的ERα突变的影响. 这表明环境中的暴露可能会影响乳腺癌的发展和治疗反应.
科学领域:
- 内分泌学 在内分泌学.
- 分子生物学分子生物学
- 环境健康 环境健康
背景情况:
- 雌激素受体α (ERα) 在乳腺癌中至关重要,ESR1中的Y537S和D538G等突变为内分泌疗法提供了耐药性.
- 金属雌激素,如,通过其联结域 (LBD) 激活ERα.
研究的目的:
- 为了研究是否会像一样激活ERα.
- 确定对构成性活性的ERα突变体 (Y537S,D538G) 的作用及其与协活性剂的相互作用.
- 探索针对乳腺癌中的-ERα相互作用的治疗潜力.
主要方法:
- 在ERα LBD上发现的/金属相互作用部位的突变分析.
- 评估ERα活性,DNA结合,以及对和雌激醇的反应中辅激剂的招募.
- 评估通道阻塞剂和化剂对癌细胞生长的影响.
主要成果:
- 通过与类似的机制激活ERα,增强Y537S和D538G突变体的构成性活性.
- 突变发现的金属相互作用点减少了构成性和诱导的ERα活性.
- 激活突变体与联合激活剂和RNA聚合酶II的相互作用发生了变化,而DNA结合保持不变.
- 通道阻断剂和化剂抑制了表达这些突变的细胞的生长.
结论:
- 激活ERα,并加剧耐药性转移突变的影响,这表明它在乳腺癌病因和进展中发挥了作用.
- 向-ERα相互作用或使用调节剂可能为内分泌抵抗性乳腺癌提供新的治疗策略.
相关概念视频
Calmodulin-dependent Signaling
5.1K
Calmodulin (CaM) is a calcium-binding protein in eukaryotes that controls various calcium-regulated cellular processes. It has four calcium-binding sites that bind calcium to form the calcium-calmodulin ( Ca2+-CaM) complex. GPCR stimulation increases the calcium levels in the cells that bind to CaM and induces a conformational change.
The Ca2+-CaM complex does not have enzymatic activity by itself. Instead, the complex binds downstream target proteins, including membrane proteins or enzymes,...
The Ca2+-CaM complex does not have enzymatic activity by itself. Instead, the complex binds downstream target proteins, including membrane proteins or enzymes,...
5.1K
GPCRs Regulate Adenylyl Cylase Activity
5.4K
Some GPCRs transmit signals through adenylyl cyclase (AC), a transmembrane enzyme. AC helps synthesize second messenger cyclic adenosine monophosphate (cAMP). AC catalyzes cyclization reaction and converts ATP to cAMP by releasing a pyrophosphate. The pyrophosphate is further hydrolyzed to phosphate by the enzyme pyrophosphatase, which drives cAMP synthesis to completion. However, cAMP is rapidly degraded to 5′ AMP by the enzymes phosphodiesterase (PDE), preventing overstimulation of...
5.4K
Transducer Mechanism: Nuclear Receptors
1.3K
Nuclear receptors, or NRs, are unique transcription factors that regulate gene transcription and affect the cellular pathways involved in reproduction, development, or metabolism. Their ability to be stimulated by small lipophilic ligands and control vital cellular processes makes them ideal drug targets. Nearly 10-15% of currently prescribed drugs target these receptors.
About 48 different soluble family members of nuclear receptors are identified that can be divided into two main classes:
About 48 different soluble family members of nuclear receptors are identified that can be divided into two main classes:
1.3K
Cell Specific Gene Expression
13.5K
Multicellular organisms contain a variety of structurally and functionally distinct cell types, but the DNA in all the cells originated from the same parent cells. The differences in the cells can be attributed to the differential gene expression. Liver cells, whose functions include detoxification of blood, production of bile to metabolize fats, and synthesis of proteins essential for metabolism, must express a specific set of genes to perform their functions. Gene expression also varies with...
13.5K
Activation and Inactivation of G Proteins
6.9K
Heterotrimeric G proteins are guanine nucleotide-binding proteins. As the name suggests, heterotrimeric G proteins are composed of three subunits: alpha, beta, and gamma. They remain GDP-bound or GTP-bound inside the cells and switch between inactive/active states. The Gα subunit possesses the nucleotide-binding pocket that binds guanine nucleotides and switches between GDP or GTP-bound states. In contrast, the Gꞵ and Gγ subunits are always bound together with high...
6.9K
Internal Receptors
69.7K
Many cellular signals are hydrophilic and therefore cannot pass through the plasma membrane. However, small or hydrophobic signaling molecules can cross the hydrophobic core of the plasma membrane and bind to internal, or intracellular, receptors that reside within the cell. Many mammalian steroid hormones use this mechanism of cell signaling, as does nitric oxide (NO) gas.
69.7K


