Efp targets 14-3-3 sigma for proteolysis and promotes breast tumour growth

Oestrogen exerts its influence on target organs through activating oestrogen receptors (ERs) and regulating downstream genes by means of their oestrogen-responsive elements. Efp, a target gene product of ER alpha, is a member of the RING-finger B-box coiled-coil (RBCC) motif family. Efp is predominantly expressed in various female organs as well as in breast cancers, and is thought to be essential for oestrogen-dependent cell proliferation and organ development Efp-disrupted mice display underdeveloped uteri and reduced oestrogen responsiveness. Here we show that Efp is a RING-finger-dependent ubiquitin ligase (E3) that targets proteolysis of 14-3-3 sigma, a negative cell cycle regulator that causes G2 arrest. We demonstrate that tumour growth of breast cancer MCF7 cells implanted in female athymic mice is reduced by treatment with antisense Efp oligonucleotide. Efp-overexpressing MCF7 cells in ovariectomized athymic mice generate tumours in the absence of oestrogen. Loss of Efp function in mouse embryonic fibroblasts results in an accumulation of 14-3-3 sigma, which is responsible for reduced cell growth. These data provide an insight into the cell-cycle machinery and tumorigenesis of breast cancer by identifying 14-3-3 sigma as a target for proteolysis by Efp, leading to cell proliferation.     

Human oestrogen receptor cDNA: sequence, expression and homology to v-erb-A

We have cloned and sequenced the complete complementary DNA of the oestrogen receptor (ER) present in the breast cancer cell line MCF-7. The expression of the ER cDNA in HeLa cells produces a protein that has the same relative molecular mass and binds oestradiol with the same affinity as the MCF-7 ER. There is extensive homology between the ER and the erb-A protein of the oncogenic avian erythroblastosis virus.     

G-protein-coupled receptor heterodimerization modulates receptor function.

The opioid system modulates several physiological processes, including analgesia, the stress response, the immune response and neuroendocrine function. Pharmacological and molecular cloning studies have identified three opioid-receptor types, delta, kappa and mu, that mediate these diverse effects. Little is known about the ability of the receptors to interact to form new functional structures, the simplest of which would be a dimer. Structural and biochemical studies show that other G-protein-coupled receptors (GPCRs) interact to form homodimers. Moreover, two non-functional receptors heterodimerize to form a functional receptor, suggesting that dimerization is crucial for receptor function. However, heterodimerization between two fully functional receptors has not been documented. Here we provide biochemical and pharmacological evidence for the heterodimerization of two fully functional opioid receptors, kappa and delta. This results in a new receptor that exhibits ligand binding and functional properties that are distinct from those of either receptor. Furthermore, the kappa-delta heterodimer synergistically binds highly selective agonists and potentiates signal transduction. Thus, heterodimerization of these GPCRs represents a novel mechanism that modulates their function.     

双酚A类同系物的雌激素效应及对MCF-7细胞的毒性

双酚A(bisphenol A, BPA)及其类似物作为聚碳酸酯的主要合成原料, 一直是环境污染的重要问题, 其环境分布及人体暴露是当今科学研究的热点. 为评估环境中BPA 类物质的毒性效应, 采用MTT 比色法检测了7 种BPA 类同系物对人雌激素受体(estrogen receptor,ER)缺失乳腺癌细胞MCF-7(ER–) 增殖活性的影响. 通过检测细胞乳酸脱氢酶(lactate dehydrogenase, LDH)露出率评估了目标物对MCF-7 细胞膜的损伤, 结果表明, 在0.01～1.00 μmol/L 浓度范围内, 受试化合物对MCF-7 细胞的毒性较小, LDH 少量露出; 而在10 和100 μmol/L 浓度下, 细胞增殖受到显著抑制, 细胞膜通透性显著改变, LDH大量露出. 同时采用ER 基因双杂交酵母实验检验了这几种BPA 类同系物的雌激素效应大小, 通过Logistic 模型对曲线进行了拟合, 并以模型估算的半数透导活性(EC50) 评估了7 种BPA 类同系物的雌激素效应活性, 其大小依次为TDP>BPAF>4Cl-BPA>BPC>BPA>BPE>BPAP. 这说明其雌激素效应机制可能是通过和ER 结合而产生的.     

Hypomethylation-linked activation of PAX2 mediates tamoxifen-stimulated endometrial carcinogenesis

Tamoxifen, a selective oestrogen receptor modulator, has been used in the treatment of all stages of hormone-responsive breast cancer. However, tamoxifen shows partial oestrogenic activity in the uterus and its use has been associated with an increased incidence of endometrial cancer. The molecular explanation for these observations is not known. Here we show that tamoxifen and oestrogen have distinct but overlapping target gene profiles. Among the overlapping target genes, we identify a paired-box gene, PAX2, that is crucially involved in cell proliferation and carcinogenesis in the endometrium. Our experiments show that PAX2 is activated by oestrogen and tamoxifen in endometrial carcinomas but not in normal endometrium, and that this activation is associated with cancer-linked hypomethylation of the PAX2 promoter.     

生活垃圾焚烧飞灰的污染特性

垃圾焚烧会产生含重金属等污染物的烟气净化系统飞灰 .根据上海浦东新区生活垃圾焚烧厂飞灰的重金属和溶解盐测试分析结果 ,以及国外对飞灰中二口恶口英等有机污染物的研究 ,分析了我国垃圾焚烧飞灰的污染特性 .研究结果表明 :按我国危险废物浸出毒性鉴别标准 ,飞灰属危险废物 ;Pb ,Cd ,Hg和Zn是飞灰中的主要重金属污染元素 ;可浸出部分Cd主要以离子交换态和酸溶态形式存在 ,而Pb和Zn主要以酸溶态形式存在 ,因此在酸性环境条件下飞灰的重金属污染风险会显著增加 .飞灰溶解盐为 2 2 .1% ,主要为氯化物 ,其存在会增大其它污染物的溶解度 ;飞灰处置时可能会污染地下水体 .飞灰含少量二口恶口英和呋喃等有机污染物 ,有污染环境和危害人类健康的风险     

环境污染物的抗雌激素效应及机制研究进展

 列举了10 余种具有抗雌激素效应的环境污染物, 从拮抗E₂水平、拮抗E₂功能、拮抗雌性性征3 个方面阐释了这些物质的抗雌激素效应, 并进一步论述了其在E₂合成、运输、受体结合及代谢等方面发挥抗雌激素效应的机制。展望了环境污染物的抗雌激素效应及相关机制的研究方向。     

二恶英的毒性、健康风险及对策

介绍了二恶英及其类似化合物对人的毒性、致毒机理和健康风险。由于它们能在环境中长期存在,并能在动物和人体组织中生物累积,所以二恶英及类二恶英物质对动物和人体有一系列强毒性,例如:致癌性、致畸致突变性、繁育受阻、免疫力下降等。二恶英类化合物作为芳香烃受体激活剂,能够某种程度上改变细胞生长和发育的途径而导致种种影响,比如癌症、对动物乃至对人类繁衍和发育的不利影响、新陈代谢功能紊乱及免疫力下降以致出现种种疾病症候甚至感染艾滋病。同时,探讨了在我国控制二恶英污染和毒害的方针和举措。