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The erα/KDM6B regulatory axis modulates osteogenic differentiation in human mesenchymal stem cells

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Bone Research 2022年第1期10卷 95-106页

作者： Zhenqing Liu Hye-Lim Lee Jin Sook Suh Peng Deng Chang-Ryul Lee Olga Bezouglaia Mojan Mirnia Vivian Chen Michael Zhou Zhong-Kai Cui Reuben HKim Min Lee Tara Aghaloo Christine Hong Cun-Yu Wang Division of Oral Biology and Medicine School of DentistryUniversity of CaliforniaLos Angeles(UCLA)Los AngelesCA 90095USA Department of Anatomy&Neurobiology University of CaliforniaIrvine(UCI)IrvineCA 92697USA Department of Orofacial Sciences School of DentistryUniversity of CaliforniaSan Francisco(UCSF)San FranciscoCA 94143USA School of Dentistry University of CaliforniaSan Francisco(UCSF)San FranciscoCA 94143USA Division of Diagnostic and Surgical Sciences School of DentistryUniversity of CaliforniaLos Angeles(UCLA)Los AngelesCA 90095USA School of Dentistry University of CaliforniaLos Angeles(UCLA)Los AngelesCA 90095USA Division of Advanced Prosthodontics School of DentistryUniversity of CaliforniaLos Angeles(UCLA)Los AngelesCA 90095USA Division of Constitutive and Regenerative Sciences School of DentistryUniversity of CaliforniaLos Angeles(UCLA)Los AngelesCA 90095USA Department of Bioengineering University of CaliforniaLos Angeles(UCLA)Los AngelesCA 90095USA

Osteoporosis is a highly prevalent public health burden associated with an increased risk of bone fracture, particularly in aging women. Estrogen, an important medicinal component for the preventative and therapeutic treatment of postmenopausal osteoporosis, induces osteogenesis by activating the estrogen receptor signaling pathway and upregulating the expression of osteogenic genes, such as bone morphogenetic proteins(BMPs). The epigenetic regulation of estrogen-mediated osteogenesis,however, is still unclear. In this report, we found that estrogen significantly induced the expression of lysine-specific demethylase 6B(KDM6B) and that KDM6B depletion by shRNAs led to a significant reduction in the osteogenic potential of ***, upon estrogen stimulation, estrogen receptor-α(erα) was recruited to the KDM6B promoter, directly enhancing KDM6B expression. Subsequently, KDM6B was recruited to the BMP2 and HOXC6 promoters, resulting in the removal of H3K27me3 marks and activating the transcription of BMP2 and HOXC6, the master genes of osteogenic differentiation. Furthermore, we found that estrogen enhanced DMSC osteogenesis during calvarial bone regeneration and that estrogen’s pro-osteogenic effect was dependent on KDM6B in vivo. Taken together, our results demonstrate the vital role of the erα/KDM6B regulatory axis in the epigenetic regulation of the estrogen-dependent osteogenic response.

关键词： expression stimulation erα

Exposure to PM2.5 Enhances the PI3K/AKT Signaling and Malignancy of erα Expression-dependent Non-small Cell Lung Carcinoma

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Biomedical and Environmental Sciences 2021年第4期34卷 319-323页

作者： TIAN Lei LI Ying LIU Huan Liang LAI Wen Qing SHI Yue LIU Xiao Hua XI Zhu Ge LIN Ben Cheng Tianjin Institute of Environmental and Operational Medicine Tianjin 300050China The Third Surgical Department of Breast Cancer Tianjin Medical University Cancer Institute and HospitalTianjin 300070China

Atmospheric particulate matter(PM)2.5 is a major carcinogen and is associated with an increased risk of developing various cancers and pulmonary fibrous diseases[1-2].Non-small cell lung cancer(NSCLC)is the major type of lung cancer with high morbidity and mortality *** studies report that the incidence of NSCLC,particularly adenocarcinoma,significantly differs with the gender[3].Female patients with NSCLC have unique epidemiologic characteristics,imaging profiles,clinical manifestations,and pathological characteristics[4].

关键词： PI3K/AKT NSCLC erα

Cyclic biaxial tensile strain enhances osteogenic differentiation in rat bone marrow-derived mesenchymal stem cells via activating erα-Wnt3a/β-catenin pathway

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BIOCELL 2022年第6期46卷 1465-1472页

作者： MIN TANG XUELING HE XINGHONG YAO JIRUI WEN MINGYUE BAO LIANG LI Institute of Biomedical Engineering School of Preclinical and Forensic MedicineSichuan UniversityChengdu610041China Laboratory Animal Center of Sichuan University Chengdu610041China

The present study was designed to investigate the role of estrogen receptorα(erα)in biaxial tensile strain(BTS)regulated osteogenic differentiation of rat bone marrow-derived mesenchymal stem cells(rBMSCs).rBMSCs were derived fromrats and overexpressed erα.The rBMSCs were subjected to BTS at 1Hz with a strain of 2%for 4 h per day,3 days,with or without erαinhibitor ICI 182,780(ICI).Then,bone mineralization was performed by Alizarin Red *** markers of osteogenic differentiation and downstream Wnt3a/β-catenin signaling were detected by western *** showed that BTS enhanced the osteogenic differentiation of rBMSCs,increased protein expression levels of alkaline phosphatase(ALP),runt-related transcription factor 2(Runx2),collagen type I(Col I)and osteocalcin(OCN),and it increased the protein expression levels of estrogen receptor(er)α(erα),Wnt3a,andβ-*** The activated Wnt3a/β-catenin signaling pathway induced by BTS was abolished by ICI 182,780(ICI).In addition,overexpressing erαin rBMSCs promoted the osteogenic differentiation by *** together,BTS induced osteogenic differentiation of rBMSCs via the erαand downstream canonical Wnt3a/β-catenin pathway.

关键词： BMSCs BTS Osteogenic differentiation erα Wnt pathway

Chaperone-mediated autophagy targeting chimeras (CMATAC) forthe degradation of erα in breast cancer

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BIOCELL 2020年第4期44卷 591-595页

作者： JUN ZHANG YEHONG HUANG WENZHUO LIU LULU LI LIMING CHEN Jiangsu Key Laboratory for Molecular and Medical Biotechnology Department of BiochemistrySchool of Life SciencesNanjing Normal UniversityNanjing210023China

Estrogen receptor alpha(erα/ESR1)is overexpressed in over half of all breast cancers and is considered a valuable therapeutic target in erαpositive breast ***,we designed a membrane-permeant Chaperonemediated Autophagy Targeting Chimeras(CMATAC)peptide to knockdown endogenous erαprotein through chaperone-mediated *** peptide contains a cell membrane-penetrating peptide(TAT)that allows the peptide to by-pass the plasma membrane,anαI peptide as a protein-binding peptide(PBD)that binds specifically to erα,and CMA-targeting peptide(CTM)that targeting chaperone-mediated *** validated that erαtargeting peptide was able to target and degrade erαto reduce the viability of erαpositive breast cancer *** together,our studies provided a new method to reduce the level of intracellular erαprotein via CMATAC,and thus may provide a new strategy for the treatment of erαpositive breast cancer.

关键词： Chaperone-mediated Autophagy Targeting Chimeras (CMATAC) Breast cancer Peptide erα

人雌激素受体erα/erβ在大肠杆菌中的表达

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药学学报 2012年第10期47卷 1399-1402页

作者：罗璐赵淑娟王峥涛胡之璧上海中医药大学中药研究所国家中医药管理局中药新资源和品质评价重点研究室上海复方中药重点实验室上海201203

雌激素主要通过与雌激素受体（estrogen receptor,er）结合而发挥作用,er是一类有配体激活的核转录因子。er分为erα和erβ两种亚型,它们在人体内具体表达部位不同,发挥的功能也有所不同。

关键词：雌激素受体重组蛋白表达 erα erβ

梭鱼和青鳉鱼erα介导的雌激素活性比较研究

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中国环境科学 2010年第11期30卷 1490-1495页

作者：郝丽妮赵砚彬彭辉黄崇陈树林胡建英西北农林科技大学动物医学院陕西杨凌712100 北京大学城市与环境学院北京100871

为从物种雌激素受体(erα)敏感性差异的角度探索辽东湾野生梭鱼雌雄同体高发生率的一个可能原因,从梭鱼肝脏cDNA中扩增出长1113bp的梭鱼erα(serα)DEF区片段,并以此构建pGBT9-serαDEF质粒,将其和pGAD424-TIF2质粒依次转入Y190酵母细胞... 详细信息

为从物种雌激素受体(erα)敏感性差异的角度探索辽东湾野生梭鱼雌雄同体高发生率的一个可能原因,从梭鱼肝脏cDNA中扩增出长1113bp的梭鱼erα(serα)DEF区片段,并以此构建pGBT9-serαDEF质粒,将其和pGAD424-TIF2质粒依次转入Y190酵母细胞中,建立了serα物种特异性的酵母双杂交筛选系统.在此系统中测试了4种环境中主要的雌激素雌酮(E1)、17β-雌二醇(E2)、雌三醇(E3)及17α-炔雌醇(EE2)对梭鱼erα的诱导活性,半数雌激素活性浓度(EC50)为3.7、2.4、1698.7、1.2nmol/L,分别是青鳉鱼erα活性的4.6、2.3、3.4、3.3倍,说明梭鱼erα对E1、E2、E3、EE2具有较高的敏感性,这为解释辽东湾梭鱼雌雄同体的高发生现象提供了重要线索.

关键词： erα 梭鱼酵母双杂交测试物种敏感性

基于哺乳动物单杂交技术erα调节剂高通量筛选模型的建立及应用

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生物工程学报 2009年第7期25卷 1088-1094页

作者：张倩水小溪范玉玲郝伟丽郑智慧路新华赵宝华张华贺建功河北师范大学生命科学学院石家庄050016 华北制药集团新药开发有限责任公司石家庄050013

雌激素受体α(Estrogen receptor α,erα)是一种类固醇核受体,在机体的多种生理功能中起关键作用。为了筛选新的erα调节剂,本研究建立一个基于哺乳动物单杂交的报告基因技术的高通量erα调节剂筛选模型。利用RT-PCR技术从脂肪组织总RN... 详细信息

雌激素受体α(Estrogen receptor α,erα)是一种类固醇核受体,在机体的多种生理功能中起关键作用。为了筛选新的erα调节剂,本研究建立一个基于哺乳动物单杂交的报告基因技术的高通量erα调节剂筛选模型。利用RT-PCR技术从脂肪组织总RNA中扩增erα配体结合区(Ligand binding domain,erαLBD)基因序列,并插入含GAL4DNA结合域的pBIND-GAL4表达质粒构建pBIND-GAL4-erα(LBD)的嵌合表达质粒。该质粒与本室已构建好的含GAL4响应元件和荧光素酶的报告质粒pGL3-GAL4共转染,通过测定荧光素酶的活性评价er调节剂的转录调剂的活性。经过多种条件优化,激动剂阳性药对照雌二醇可以剂量依赖地诱导荧光素酶的表达,最大上调倍增数可达28.1倍,EC50为0.17μmol/L。拮抗剂阳性对照它莫昔芬可以有效地拮抗雌二醇的活性,最大下调倍数为6.3倍,EC50为0.1μmol/L。该筛选模型可微量化于384孔板,且Z'因子均大于0.5。利用该模型从2000多个微生物和植物来源的天然产物以及合成化合物中筛选得到4个erα激动剂。该模型灵敏、稳定,可以快速进行多种来源的erα调节剂的筛选和活性评价。

关键词： erα 激动剂拮抗剂共转染高通量筛选

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erα辅调节因子在乳腺癌中的双重调控作用

中国细胞生物学学报 2014年第10期36卷 1437-1442页

作者：许兆伟赵锋伍会健大连理工大学生命科学与技术学院大连116024

在发达国家,乳腺癌一直是威胁女性健康的恶性肿瘤之一。雌激素受体α(estrogen receptor alpha,erα)是一种配体依赖性的转录因子,其介导的基因转录调控在乳腺癌的增殖、分化、侵袭和转移等过程中发挥重要作用。erα主要依赖于辅调节因... 详细信息

在发达国家,乳腺癌一直是威胁女性健康的恶性肿瘤之一。雌激素受体α(estrogen receptor alpha,erα)是一种配体依赖性的转录因子,其介导的基因转录调控在乳腺癌的增殖、分化、侵袭和转移等过程中发挥重要作用。erα主要依赖于辅调节因子共同调控下游靶基因的表达。近年来,有研究证实,一些关键转录辅调节因子在调节er转录活性的同时,也可以作为泛素E3连接酶,促进erα的降解。该文详细介绍几种辅调节因子对erα的双重调节作用,有助于从分子水平阐明不同类型乳腺癌中造成erα表达量差异的机制,为乳腺癌的靶向治疗和预防提供理论依据。

关键词： erα 辅调节因子乳腺癌转录调控泛素E3连接酶

金雀黄素对子宫内膜癌细胞erα和erβmRNA水平的调节

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北京大学学报（医学版） 2005年第3期37卷 278-280页

作者：薛晓鸥魏丽惠北京大学人民医院妇科北京100044

目的:研究金雀黄素对子宫内膜癌细胞erα,erβmRNA的调节作用,探讨植物雌激素对子宫内膜癌的作用机制,为临床应用植物雌激素提供理论依据。方法:体外培养子宫内膜癌细胞系Ishikawa,采用实时荧光定量RT PCR方法,观察不同剂量金雀黄素对... 详细信息

目的:研究金雀黄素对子宫内膜癌细胞erα,erβmRNA的调节作用,探讨植物雌激素对子宫内膜癌的作用机制,为临床应用植物雌激素提供理论依据。方法:体外培养子宫内膜癌细胞系Ishikawa,采用实时荧光定量RT PCR方法,观察不同剂量金雀黄素对两种雌激素亚型表达的影响,阳性对照为雌二醇、孕酮作用组。结果: (1)低剂量金雀黄素能提高子宫内膜癌细胞erαmRNA表达,但其作用较雌二醇明显弱;低剂量金雀黄素能降低erβmRNA的表达,而雌二醇对erβmRNA作用不明显。(2)高剂量金雀黄素的作用与孕酮相似,能下调子宫内膜癌细胞erαmRNA和erβmRNA表达,但较孕酮作用弱。结论:金雀黄素对子宫内膜癌细胞erαmRNA和erβmRNA的表达作用不同,而且与其剂量有一定关系。推测金雀黄素有雌激素受体调节剂的作用。

关键词：金雀黄素 erβ mRNA水平 erα 定量RT-PCR方法雌激素受体调节剂 mRNA表达植物雌激素 αmRNA 子宫内膜癌雌二醇调节作用作用机制临床应用癌细胞系体外培养实时荧光亚型表达不同剂量阳性对照表达作用低剂量