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Targeted oncogenesis reveals a distinct tissue-specific utilization of alternative promoters of the human mineralocorticoid receptor gene in transgenic mice

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JOURNAL OF BIOLOGICAL CHEMISTRY 2000年第11期275卷 7878-7886页

作者： Le Menuet, D Viengchareun, S Penfornis, P Walker, F Zennaro, MC Lombès, M Fac Xavier Bichat INSERM U478 Inst Federatif Rech Cellules Epitheliales F-75870 Paris 18 France Hop Bichat Claude Bernard Serv Anatomopathol F-75018 Paris France

The human mineralocorticoid receptor (hMR) is a nuclear receptor mediating aldosterone action, whose expression is driven by two alternative promoters, P1 and P2, flanking the two first 5'-untranslated exons. In vivo characterization of hMR regulatory regions was performed by targeted oncogenesis in mice using PI or Pa directing expression of the large T antigen of SV40 (TAg). While transgenic *** founders rapidly developed lethal hibernomas from brown fat, cerebral primitive neuroectodermal tumors and facial leiomyosarcomas occurred in *** mice. Quantitative analyses of mouse MR (mMR) and transgene expression indicate that P1 promoter was transcriptionally active in all MR-expressing tissues, directing strong TAg expression in testis and salivary glands, moderate in lung brain, uterus, liver, and heart but, unlike mMR, rather low in colon and kidney. Importantly, the renal transgene expression colocalized with mMR in the distal nephron. In contrast, P2 promoter was approximately 10 times less potent than P1, with no activity in the brain and colon. Several immortalized cell lines were established from both neoplastic and normal tissues of transgenic mice. These cells exhibited differentiated characteristics and maintained MR expression, thus providing useful models for further studies exploring the widespread expression and functions of MR. Our results demonstrate that hMR gene expression in vivo is controlled by complex regulatory mechanisms involving distinct tissue-specific utilization of alternative promoters.

关键词：脂肪组织棕色/病理学抗原病毒肿瘤/遗传学脑/病理学细胞转化肿瘤/遗传学基因表达调控肿瘤平滑肌肉瘤/遗传学平滑肌肉瘤/病理学脂肪瘤/遗传学脂肪瘤/病理学小鼠转基因盐皮质激素类/代谢神经外胚瘤/遗传学神经外胚瘤/病理学表型启动区遗传 RNA 信使/分析受体盐皮质激素/遗传学受体盐皮质激素/代谢信号传导猴病毒40 组织分布动物人类小鼠

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Activating mineralocorticoid receptor mutation in hypertension exacerbated by pregnancy

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SCIENCE 2000年第5476期289卷 119-123页

作者： Geller, DS Farhi, A Pinkerton, N Fradley, M Moritz, M Spitzer, A Meinke, G Tsai, FTF Sigler, PB Lifton, RP Yale Univ Sch Med Boyer Ctr Mol Med Howard Hughes Med Inst New Haven CT 06510 USA Yale Univ Sch Med Boyer Ctr Mol Med Dept Genet New Haven CT 06510 USA Yale Univ Sch Med Boyer Ctr Mol Med Dept Internal Med Nephrol New Haven CT 06510 USA Yale Univ Sch Med Boyer Ctr Mol Med Dept Mol Biophys & Biochem New Haven CT 06510 USA Yeshiva Univ Albert Einstein Coll Med Dept Pediat Bronx NY 10461 USA

Hypertension and pregnancy-related hypertension are major public health problems of largely unknown causes. We describe a mutation in the mineralocorticoid receptor (MR), S810L, that causes early-onset hypertension that is markedly exacerbated in pregnancy. This mutation results in constitutive MR activity and alters receptor specificity, with progesterone and other steroids lacking 21-hydroxyl groups, normally MR antagonists, becoming potent agonists. Structural and biochemical studies indicate that the mutation results in the gain of a van der Waals interaction between helix 5 and helix 3 that substitutes for interaction of the steroid 21-hydroxyl group with helix 3 in the wild-type receptor. This helix 5-helix 3 interaction is highly conserved among diverse nuclear hormone receptors, suggesting its general role in receptor activation.

关键词：醛固酮/代谢氨基酸序列氨基酸取代碱基序列结合竞争性二聚作用杂合子高血压/病因学高血压/遗传学高血压/代谢模型分子分子序列数据系谱点突变妊娠并发症心血管/病因学妊娠并发症心血管/代谢孕酮/代谢蛋白质构象蛋白质结构二级受体盐皮质激素/化学受体盐皮质激素/遗传学受体盐皮质激素/代谢受体类固醇/化学受体类固醇/代谢甾类/代谢青少年女(雌)性人类男(雄)性妊娠

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Rapid nongenomic effects of aldosterone in mineralocorticoid-receptor-knockout mice

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BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS 1999年第1期266卷 257-261页

作者： Haseroth, K Gerdes, D Berger, S Feuring, M Günther, A Herbst, C Christ, M Wehling, M Univ Heidelberg Klinikum Mannheim Fac Clin Med Inst Clin Pharmacol D-68167 Mannheim Germany Univ Heidelberg Klinikum Mannheim Fac Clin Med Dept Dermatol D-68167 Mannheim Germany German Canc Res Ctr Div Mol Biol Cell 1 Heidelberg Germany

In addition to genomic effects of aldosterone, rapid nongenomic effects of steroids have been reported in various tissues that were clearly incompatible with a genomic action of aldosterone, Rapid effects of aldosterone involve second messengers such as calcium and cAMP. Specific high affinity binding sites for aldosterone have been characterized in membranes for different cells, which probably transmit those rapid steroid effects. To date, it is unclear if these binding sites are modified classical mineralocorticoid receptors (MR) or if they represent an unrelated receptor protein. The aim of the present study was to investigate whether rapid aldosterone action still occurs in the absence of the classical MR. For this purpose we used the model of MR knockout mice. Rapid effects were analyzed in skin cells, measuring intracellular calcium and cAMP levels after stimulation with aldosterone. We found that rapid effects are not only present in MR knockout mice, but that the effects are even larger than in wild-type mice cells. The results of the present study demonstrate that the classic MR is dispensable for rapid aldosterone action. The study, thus, proves that a receptor different from the classic intracellular receptor is involved in rapid aldosterone signaling. (C) 1999 Academic Press.

关键词：醛固酮/药理学钙/代谢钙信号/药物作用细胞培养的环AMP/代谢基因缺失小鼠基因敲除受体盐皮质激素/遗传学受体盐皮质激素/生理学皮肤/细胞学皮肤/药物作用皮肤/代谢时间因素动物小鼠

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Two inbred strains of rats, Fischer 344 and Lewis, showed differential behavior and brain expression of corticosterone receptor mRNA induced by methamphetamine

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NEUROBIOLOGICAL MECHANISMS OF DRUGS OF ABUSE: COCAINE, IBOGAINE, AND SUBSTITUTED AMPHETAMINES 2000年第1期914卷 33-45页

作者： Numachi, Y Yoshida, S Toda, S Matsuoka, H Sato, M Tohoku Univ Grad Sch Med Dept Psychiat Sendai Miyagi 9808574 Japan Univ Michigan Mental Hlth Res Inst Ann Arbor MI 48109 USA

Recently, a role of the hypothalamo-pituitary-adrenocortical (HPA) axis in facilitating the behavioral and neurochemical effects of psychostimulants has been proposed. Two inbred strains of rats, Fischer 344/N (F344) and Lewis/N (LEW), have markedly different HPA axes as well as behavioral responses to psychostimulants: F344 rats show hyperresponsive BPA axis and no significant sensitization to cocaine, whereas LEW rats display blunted response in HPA axis and develop cocaine-induced locomotor sensitization. Corticosterone exerts its biological effects via intracellular receptors, termed type I (mineralocorticoid receptor: MR) and type II (glucocorticoid receptor: GR). The present study examines the development of stereotypy sensitization and the brain expression of mRNAs for MR, GR, and heat shock protein 90 (HSP90) in methamphetamine (MAP)-treated F344 and LEW rats. Animals received i.p. injections with chronic saline (SAL: once daily for 21 days), chronic saline and acute MAP (AM: saline for 20 days and 4 mg/kg MAP on the 21st day), or chronic MAP (CM: 4 mg/kg MAP for 21 days) and were sacrificed three hours after the last injections. Striatum, hippocampus, and cerebellum were quickly dissected on ice and total RNA was isolated for northern analyses. LEW rats developed stereotypy sensitization significantly earlier than F344 rats. AM significantly decreased GR and MR mRNA expression in hippocampus of LEW, compared to SAL. CM significantly increased GR and MR mRNA expression in striatum of F344 compared to SAL and AM, while it decreased GR mRNA in striatum of LEW and MR mRNA in hippocampus, compared to SAL. AM significantly increased HSP90 mRNA in all brain regions examined, without the hippocampus in LEW. CM significantly increased the expression of HSP90 mRNA in the striatum and cerebellum of F344, but significantly decreased in the striatum and hippocampus of LEW. These contrasting differences between F344 and LEW, in their susceptibility to stereotypy sensitiz

关键词：行为动物/药物作用印迹法 RNA/方法体温/药物作用脑/解剖学和组织学脑/药物作用脑/代谢中枢神经系统刺激剂/投药和剂量用药计划表基因表达/药物作用 HSP90热休克蛋白质类/遗传学 HSP90热休克蛋白质类/代谢甲基苯丙胺/投药和剂量大鼠近交F344 大鼠近交Lew 受体糖皮质激素/遗传学受体糖皮质激素/代谢受体盐皮质激素/遗传学受体盐皮质激素/代谢受体类固醇/遗传学受体类固醇/代谢种特异性刻板行为/药物作用时间因素动物男(雄)性大鼠

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A single amino acid mutation of Ala-773 in the mineralocorticoid receptor confers agonist properties to 11β-substituted spirolactones

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MOLECULAR PHARMACOLOGY 2000年第4期58卷 684-691页

作者： Auzou, G Fagart, J Souque, A Hellal-Lévy, C Wurtz, JM Moras, D Rafestin-Oblin, ME INSERM U439 F-34090 Montpellier France Inst Genet & Biol Mol & Cellulaire Illkirch CU Strasbourg France Fac Med Xavier Bichat Inst Federatif Rech 02 INSERM U478 Paris France

Sequence analysis revealed a strong homology between the ligand-binding domain (LBD) of the human mineralocorticoid receptor (hMR) and glucocorticoid receptor (hGR). Nevertheless, steroids with bulky C11-substituents bind to hGR, unlike hMR. In this report, a mutant hMR, in which the residue Ala-773 facing the C11 steroid position was replaced by a glycine (A773G), was assayed for its capacity to bind steroids, to interact with receptor coactivators, and to stimulate transcription. The capacity of A773G to bind aldosterone and C11-substituted spirolactones was the same as that of the wild-type receptor. The agonist properties of aldosterone, as well as the antagonist feature of compounds bearing a 11 beta-allenyl group and a C17-ketone function, remain unchanged. In contrast, C11-substituted steroids with a 17 gamma-lactonic ring displayed antagonist properties with hMR and acted as potent agonists with A773G. An agonist-dependent hMR interaction with SRC-1 was observed for both the wild-type and the mutant receptors. The hMR activation process is discussed in the light of the hMR-LBD homology model based on the structural data of the human progesterone receptor LBD.

关键词：丙氨酸/遗传学丙氨酸/代谢氨基酸序列氨基酸取代 COS细胞组蛋白酰基转移酶模型分子分子序列数据诱变定点核受体共激活因子1 受体盐皮质激素/激动剂受体盐皮质激素/遗传学受体盐皮质激素/代谢序列同源性氨基酸螺内酯/类似物和衍生物螺内酯/药理学转录因子/代谢转录激活动物人类

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Characterization of transactivational property and coactivator mediation of rat mineralocorticoid receptor activation function-1 (AF-1)

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MOLECULAR ENDOCRINOLOGY 2000年第6期14卷 889-899页

作者： Fuse, H Kitagawa, H Kato, S Univ Tokyo Inst Mol & Cellular Biosci Bunkyo Ku Tokyo 1130032 Japan Teikoku Hormone Mfg Co Pharmacol Res Dept Tokyo 1078522 Japan

The autonomous activation function-2 (AF-2) in the mineralocorticoid receptor (MR) UF domain is known to play a major role in the ligand-induced transactivation function of MR;however, it remained unclear about the transactivation function of its A/B domain. We therefore tried to characterize the MR A/B domain as the AF-1 and further studied the actions of known coactivators for AF-2 in the E/F ligand-binding domain in the function of the MR A/B domain. Deletion analyses of rat and human MRs revealed that the A/B domains harbor a transactivation function acting as AF-1. The MR mutant (E959Q) with a point mutation in helix 12, which causes a complete loss of MR AF-2 activity, still retained ligand-induced transactivation function, indicating a significant role for AF-1 in the full activity of the ligand-induced MR function. Among the coactivators tested to potentiate the MR AF-2, TIF2 and p300 potentiated the MR AF-1 through two different core regions [amino acids (a.a.) 1-169, a.a. 451-603] and exhibited functional interactions with the MR A/B domain in the cultured cells. However, such interactions were undetectable in a yeast and in an in vitro glutathione-S-transferase pull-down assay, indicating that the functional interaction of TIF2 and p300 with the MR A/B domain to support the MR AF-1 activity require some unknown nuclear factor(s) or a proper modification of the A/B domain in the cells.

关键词：印迹法蛋白质 COS细胞 E1A相关p300蛋白质大肠杆菌/遗传学基因缺失遗传载体谷胱甘肽转移酶/遗传学核蛋白质类/代谢核蛋白质类/药理学核受体共激活因子2 点突变受体盐皮质激素/化学受体盐皮质激素/遗传学受体盐皮质激素/生理学重组融合蛋白质类酵母菌酿酒/遗传学构效关系反式激活(遗传学) 反式激活因子类/代谢反式激活因子类/药理学转录因子/代谢转录因子/药理学转染动物人类大鼠

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Paradoxical effects of mineralocorticoids on the ion gated sodium channel in embryologically diverse cells

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BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS 2000年第3期270卷 811-815页

作者： Mirshahi, M Golestaneh, N Valamanesh, F Agarwal, MK Ctr Univ Cordeliers INSERM U9912 Paris France CNRS UMR 8532 Dept Biol & Pharmacol Struct F-94200 Ivry France

PCR analysis and Western blotting revealed the expression of the mineralocorticoid receptor (MCR) and the epithelial sodium channel (ENaC) genes at the level of RNA, DNA, and protein in several leukemic cell lines, fibroblasts from human cornea, and epithelial cells from ocular tissues. Following immunofluorescence, the MCR appeared to be primarily nuclear whereas the ENaC was almost exclusively membrane-bound. Paradoxically, the MCR-specific antagonist ZK 91587 actually stimulated the multiplication of human erythroblastic leukemia cells, contrary to the inhibitory effect of the antagonist RU 26752 on the multiplication of corneal fibroblasts;both effects were opposed by aldosterone, In quantitative PCR, both basal and aldosterone-induced levels of ENaC were diminished by ZK 91587 in the corneal fibroblast, in contrast to the stimulation observed in the retinal pigmentary epithelium, Thus, contrary to the existing notions, (a) antimineralocorticoids can act both as agonists and antagonists, and (b) the receptor-mediated action of mineralocorticoids on the sodium channel is not restricted to the epithelial cell. (C) 2000 Academic Press.

关键词：醛固酮/药理学细胞分裂/药物作用细胞培养的角膜/细胞学角膜/药物作用角膜/生理学上皮钠通道成纤维细胞/细胞学成纤维细胞/药物作用成纤维细胞/生理学离子通道闸门/药物作用白血病幼红细胞急性盐皮质激素类/拮抗剂和抑制剂盐皮质激素类/药理学色素上皮眼/细胞学色素上皮眼/药物作用色素上皮眼/生理学受体盐皮质激素/遗传学受体盐皮质激素/生理学钠通道/药物作用钠通道/遗传学钠通道/生理学螺内酯/类似物和衍生物螺内酯/药理学肿瘤细胞培养的动物牛人类

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Another piece in the hypertension puzzle

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MOLECULAR MEDICINE TODAY 2000年第10期6卷 378-379页

作者： Fricker, J

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