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1. 发明授权

US06794160B1 Hormone receptor compositions and methods 失效
标题翻译：激素受体组合物和方法
公开(公告)号：US06794160B1
公开(公告)日：2004-09-21
申请号：US08462817
申请日：1995-06-05
申请人： Ronald M. Evans , Cary A. Weinberger , Stanley M. Hollenberg , Vincent Giguere , Jeffrey Arriza , Catherine C. Thompson , Estelita S. Ong
发明人： Ronald M. Evans , Cary A. Weinberger , Stanley M. Hollenberg , Vincent Giguere , Jeffrey Arriza , Catherine C. Thompson , Estelita S. Ong
IPC分类号： C12N1512
CPC分类号： C12Q1/6897 , C07K14/721 , C07K14/723 , C12N15/67
摘要： The present invention provides substantially pure DNA's comprised of sequences which encode proteins having the hormone-binding and/or transcription-activating characteristics of a glucocorticoid receptor, a mineralocorticoid receptor, or a thyroid hormone receptor; various plasmids containing receptor sequences which exemplify these DNA's; receptor proteins, including modified functional forms thereof, expressed from these DNA's (or mRNA's); and a bioassay for determining the functionality of a receptor protein. Use of this bioassay has led to the discovery that a necessary and sufficient condition for activation of transcription of a gene (G), whose transcription is activated by hormones complexed with receptors, is the presence of the hormone and its receptor cell (C) where (G) is located. As a result, two new methods for producing desired proteins in genetically engineered cells were discovered.
摘要翻译：本发明提供基本上纯的DNA，其由编码具有糖皮质激素受体，盐皮质激素受体或甲状腺激素受体的激素结合和/或转录激活特征的蛋白质的序列组成; 含有例证这些DNA的受体序列的各种质粒; 受体蛋白，包括其修饰的功能形式，由这些DNA（或mRNA）表达; 以及用于测定受体蛋白质功能的生物测定。这种生物测定的使用已经导致发现，用于激活基因（G）的转录的必需和充分条件（G），其转录由与受体复合的激素激活，是激素及其受体细胞（C）的存在，其中（G）位于。因此，发现了两种在遗传工程细胞中产生所需蛋白质的新方法。

2. 发明授权

US06806359B1 Hormone receptor compositions and methods 失效
标题翻译：激素受体组合物和方法
公开(公告)号：US06806359B1
公开(公告)日：2004-10-19
申请号：US08464574
申请日：1995-06-05
申请人： Ronald M. Evans , Cary A. Weinberger , Stanley M. Hollenberg , Vincent Giguere , Jeffrey Arriza , Catherine C. Thompson , Estelita S. Ong
发明人： Ronald M. Evans , Cary A. Weinberger , Stanley M. Hollenberg , Vincent Giguere , Jeffrey Arriza , Catherine C. Thompson , Estelita S. Ong
IPC分类号： C12N1512
CPC分类号： C12Q1/6897 , C07K14/721 , C07K14/723 , C12N15/67
摘要： The present invention provides substantially pure DNA's comprised of sequences which encode proteins having the hormone-binding and/or transcription-activating characteristics of a glucocorticoid receptor, a mineralocorticoid receptor, or a thyroid hormone receptor. The invention also provides various plasmids containing receptor sequences which exemplify the DNA's of the invention. The invention further provides receptor proteins, including modified functional forms thereof, expressed from the DNA's (or mRNA's) of the invention. In addition to novel receptor DNA, RNA and protein compositions, the present invention involves a bioassay for determining the functionality of a receptor protein. By using our bioassay system we have discovered that a necessary and sufficient condition for activation of transcription of a gene (G), whose transcription is activated by hormones complexed with receptors, is the presence of the hormone and its receptor in the cell (C) where (G) is located. As a result of that discovery we have also invented new methods for producing desired proteins in genetically engineered cells. Two of these methods are methods of the present invention. The first is a method for inducing transcription of a gene whose transcription is activated by hormones complexed with the receptors. The second is a method for engineering a cell and increasing and controlling production of a protein encoded by a gene whose transcription is activated by hormones complexed with receptor proteins.
摘要翻译：本发明提供基本上纯的DNA，其由编码具有糖皮质激素受体，盐皮质激素受体或甲状腺激素受体的激素结合和/或转录激活特征的蛋白质的序列组成; 含有例证这些DNA的受体序列的各种质粒; 受体蛋白，包括其修饰的功能形式，由DNA（或mRNA）表达; 以及用于测定受体蛋白质功能的生物测定。这种生物测定的使用已经导致发现，用于激活基因（G）的转录的必需和充分条件（G），其转录由与受体复合的激素激活，是激素及其受体细胞（C）的存在，其中（G）位于。因此，发现了两种在遗传工程细胞中产生所需蛋白质的新方法。

3. 发明授权

US5606021A Mineralocorticoid receptor compositions and methods 失效
标题翻译：盐皮质激素受体组合物和方法
公开(公告)号：US5606021A
公开(公告)日：1997-02-25
申请号：US170085
申请日：1993-12-17
申请人： Ronald M. Evans , Cary A. Weinberger , Vincent Giguere , Jeffrey Arriza , Catherine C. Thompson , Estelita S. Ong
发明人： Ronald M. Evans , Cary A. Weinberger , Vincent Giguere , Jeffrey Arriza , Catherine C. Thompson , Estelita S. Ong
IPC分类号： C12N15/09 , C07K14/00 , C07K14/435 , C07K14/575 , C07K14/635 , C07K14/705 , C07K14/71 , C07K14/72 , C12N5/00 , C12N5/10 , C12N15/00 , C12N15/12 , C12N15/67 , C12P21/02 , C12Q1/68 , C12R1/91 , G01N33/50
CPC分类号： C12N15/67 , C07K14/721 , C07K14/723 , C12Q1/6897
摘要： The present invention provides recombinant proteins having the hormone-binding and/or transcription-activating characteristics of a mineralocorticoid receptor. The invention also provides proteins expressed from recombinant DNA encoding a naturally occurring receptor having the hormone-binding and/or transcription-activating characteristics of a mineralocorticoid receptor.
摘要翻译：本发明提供具有盐皮质激素受体的激素结合和/或转录激活特征的重组蛋白。本发明还提供由编码天然存在的受体的重组DNA表达的蛋白质，所述受体具有盐皮质激素受体的激素结合和/或转录激活特征。

4. 发明授权

US5597705A DNA encoding thyroid hormone receptor compositions and methods 失效
标题翻译：编码甲状腺激素受体组成和方法的DNA
公开(公告)号：US5597705A
公开(公告)日：1997-01-28
申请号：US165708
申请日：1993-12-10
申请人： Ronald M. Evans , Cary A. Weinberger , Stanley M. Hollenberg , Vincent Giguere , Jeffrey Arriza , Catherine C. Thompson , Estelita S. Ong
发明人： Ronald M. Evans , Cary A. Weinberger , Stanley M. Hollenberg , Vincent Giguere , Jeffrey Arriza , Catherine C. Thompson , Estelita S. Ong
IPC分类号： C12N15/09 , C07K14/00 , C07K14/435 , C07K14/575 , C07K14/635 , C07K14/705 , C07K14/71 , C07K14/72 , C12N5/00 , C12N5/10 , C12N15/00 , C12N15/12 , C12N15/67 , C12P21/02 , C12Q1/68 , C12R1/91 , G01N33/50 , C22N15/62
CPC分类号： C12N15/67 , C07K14/721 , C07K14/723 , C12Q1/6897
摘要： The present invention provides a recombinant expression system for production of functional thyroid hormone receptor protein(s). The invention also provides a method to produce thyroid hormone receptor protein(s) by culturing the cells of the invention recombinant expression system. Also provided are thyroid hormone receptor protein(s) produced by the invention method. In addition, the present invention provides recombinant DNAs comprised of sequences which encode proteins having the hormone-binding and/or transcription-activating characteristics of a thyroid hormone receptor. The invention also provides various plasmids containing receptor sequences which exemplify the DNAs of the invention. The invention further provides complementary mRNAs, cells transformed with invention DNAs, and nucleic acid probes derived from invention DNAs.
摘要翻译：本发明提供了用于产生功能性甲状腺激素受体蛋白质的重组表达系统。本发明还提供了通过培养本发明的重组表达系统的细胞产生甲状腺激素受体蛋白的方法。还提供了通过本发明方法产生的甲状腺激素受体蛋白。此外，本发明提供由编码具有甲状腺激素受体的激素结合和/或转录激活特征的蛋白质的序列组成的重组DNA。本发明还提供了含有受体序列的各种质粒，其例证了本发明的DNA。本发明还提供了补体mRNA，用本发明DNA转化的细胞，以及衍生自本发明DNA的核酸探针。

5. 发明授权

US5312732A Hormone receptor compositions and methods 失效
标题翻译：激素受体组合物和方法
公开(公告)号：US5312732A
公开(公告)日：1994-05-17
申请号：US667602
申请日：1991-03-07
申请人： Ronald M. Evans , Cary A. Weinberger , Stanley M. Hollenberg , Vincent Giguere , Jeffrey Arriza , Catherine C. Thompson , Estelita S. Ong
发明人： Ronald M. Evans , Cary A. Weinberger , Stanley M. Hollenberg , Vincent Giguere , Jeffrey Arriza , Catherine C. Thompson , Estelita S. Ong
IPC分类号： C12N15/09 , C07K14/00 , C07K14/435 , C07K14/575 , C07K14/635 , C07K14/705 , C07K14/71 , C07K14/72 , C12N5/00 , C12N5/10 , C12N15/00 , C12N15/12 , C12N15/67 , C12P21/02 , C12Q1/68 , C12R1/91 , G01N33/50 , C12N15/63
CPC分类号： C12N15/67 , C07K14/721 , C07K14/723 , C12Q1/6897
摘要： The present invention provides substantially pure DNA's comprised of sequences which encode proteins having the hormone-binding and/or transcription-activating characteristics of a glucocorticoid receptor, a mineralocorticoid receptor, or a thyroid hormone receptor. The invention also provides various plasmids containing receptor sequences which exemplify the DNA's of the invention. The invention further provides receptor proteins, including modified functional forms thereof, expressed from the DNA's (or mRNA's) of the invention. In addition to the novel receptor DNA, RNA and protein compositions, the present invention involves a bioassay for determining the functionality of a receptor protein. By using our bioassay system we have discovered that a necessary and sufficient condition for activation of transcription of a gene (G), whose transcription is activated by hormones complexed with receptors, is the presence of the hormone and its receptor in the cell (C) where (G) is located. As a result of that discovery we have also invented new methods for producing desired proteins in genetically engineered cells. Two of these methods are methods of the present invention. The first is a method for inducing transcription of a gene whose transcription is activated by hormones complexed with the receptors. The second is a method for engineering a cell and increasing and controlling production of a protein encoded by a gene whose transcription is activated by hormones complexed with receptor proteins.
摘要翻译：本发明提供了基本上纯的DNA，其由编码具有糖皮质激素受体，盐皮质激素受体或甲状腺激素受体的激素结合和/或转录激活特征的蛋白质的序列组成。本发明还提供了含有受体序列的各种质粒，其例证了本发明的DNA。本发明还提供了从本发明的DNA（或mRNA）表达的受体蛋白，包括其修饰的功能形式。除了新的受体DNA，RNA和蛋白质组合物之外，本发明涉及用于测定受体蛋白质的功能的生物测定。通过使用我们的生物测定系统，我们已经发现，激活基因（G）的转录的必要和充分条件（G），其转录由与受体复合的激素激活，是细胞中激素及其受体的存在（C）其中（G）位于。作为这一发现的结果，我们还发明了用于在遗传工程细胞中产生所需蛋白质的新方法。这些方法中的两个是本发明的方法。第一种是诱导转录由与受体复合的激素激活的基因的转录的方法。第二种是用于工程化细胞并增加和控制由受体与受体蛋白质复合的激素激活转录的基因编码的蛋白质的产生的方法。

6. 发明授权

US5071773A Hormone receptor-related bioassays 失效
标题翻译：激素受体相关生物多样性
公开(公告)号：US5071773A
公开(公告)日：1991-12-10
申请号：US108471
申请日：1987-10-20
申请人： Ronald M. Evans , Cary A. Weinberger , Stanley M. Hollenberg , Vincent Giguere , Jeffrey Arriza , Catherine C. Thompson , Estelita S. Ong
发明人： Ronald M. Evans , Cary A. Weinberger , Stanley M. Hollenberg , Vincent Giguere , Jeffrey Arriza , Catherine C. Thompson , Estelita S. Ong
IPC分类号： C12N15/09 , C07K14/00 , C07K14/435 , C07K14/575 , C07K14/635 , C07K14/705 , C07K14/71 , C07K14/72 , C12N5/00 , C12N5/10 , C12N15/00 , C12N15/12 , C12N15/67 , C12P21/02 , C12Q1/68 , C12R1/91 , G01N33/50
CPC分类号： C12N15/67 , C07K14/721 , C07K14/723 , C12Q1/6897
摘要： The present invention discloses two hormone receptor-related bioassays. The first bioassay is useful for determining whether a protein suspected of being a hormone receptor has transcription-activating properties of a hormone receptor. The second bioassay is useful for evaluating whether compounds are functional ligands for receptor proteins. According to the first bioassay, cells that contain non-endogenous DNA which expresses a protein suspected of being a hormone receptor and which contain a DNA sequence encoding an operative hormone responsive promoter/enhancer element linked to an operative reporter gene, are cultured, the culturing being conducted in a culture medium containing a known hormone, or an analog thereof. The cultured cells are then monitored for induction of the product of the reporter gene as an indication of functional transcription-activating binding between the hormone or hormone analog and the protein suspected of being a hormone receptor. According to the second bioassay, cells that contain non-endogenous DNA which expresses hormone receptor or a functional engineered or modified form thereof, and which also contain a DNA sequence encoding an operative hormone responsive promoter/enhancer element linked to an operative reporter gene, are cultured, the culturing being conducted in culture medium containing at least one compound whose ability to functionally bind the receptor protein is sought to be determined. The cultured cells are then monitored for induction of the product of the report gene as an indicator of functional binding between the compound and the receptor.
摘要翻译：本发明公开了两种与激素受体相关的生物测定。第一种生物测定可用于确定怀疑是激素受体的蛋白质是否具有激素受体的转录激活特性。第二个生物测定可用于评估化合物是否是受体蛋白质的功能性配体。根据第一生物测定法，培养含有表达怀疑是激素受体的蛋白质并含有编码与操作性报告基因连接的操作性激素反应性启动子/增强子元件的DNA序列的非内源性DNA的细胞，培养在含有已知激素或其类似物的培养基中进行。然后监测培养的细胞以诱导报告基因的产物，作为激素或激素类似物与怀疑是激素受体的蛋白质之间的功能性转录激活结合的指示。根据第二生物测定，含有表达激素受体的非内源性DNA或其功能性工程化或修饰形式的细胞，并且还包含编码与有效的报告基因连接的操作性激素反应性启动子/增强子元件的DNA序列的细胞是培养时，寻求在含有至少一种能够与受体蛋白质功能结合的化合物的培养基中进行培养。然后监测培养的细胞以诱导报告基因的产物，作为化合物和受体之间功能性结合的指标。

7. 发明授权

US5534418A Controlled expression of recombinant proteins 失效
标题翻译：重组蛋白的控制表达
公开(公告)号：US5534418A
公开(公告)日：1996-07-09
申请号：US166177
申请日：1993-12-10
申请人： Roland M. Evans , Cary A. Weinberger , Stanley M. Hollenberg , Vincent Giguere , Jeffrey Arriza , Catherine C. Thompson , Estelita S. Ong
发明人： Roland M. Evans , Cary A. Weinberger , Stanley M. Hollenberg , Vincent Giguere , Jeffrey Arriza , Catherine C. Thompson , Estelita S. Ong
IPC分类号： C12N15/09 , C07K14/00 , C07K14/435 , C07K14/575 , C07K14/635 , C07K14/705 , C07K14/71 , C07K14/72 , C12N5/00 , C12N5/10 , C12N15/00 , C12N15/12 , C12N15/67 , C12P21/02 , C12Q1/68 , C12R1/91 , G01N33/50
CPC分类号： C12N15/67 , C07K14/721 , C07K14/723 , C12Q1/6897
摘要： The present invention provides methods for the controlled production of recombinant proteins in cells. Cells employed in the invention method contain a gene encoding the desired recombinant protein, with transcription of the gene maintained under the control of a transcriptional control element which is activated by a ligand/receptor complex. The ligand/receptor complex is formed when a ligand (which is a hormone or/and analog thereof) is complexed with a receptor (which is a hormone receptor or functional analog thereof which has the transcription activating properties of the receptor). Receptor is produced by the expression of non-endogenous DNA which is also present in the cells used for production of recombinant protein.
摘要翻译：本发明提供了在细胞中控制重组蛋白质生产的方法。本发明方法中使用的细胞含有编码所需重组蛋白的基因，该基因的转录保持在由配体/受体复合物激活的转录控制元件的控制之下。当配体（其是激素或/或其类似物）与受体（其是具有受体的转录激活特性的激素受体或其功能类似物）复合时，形成配体/受体复合物。受体是由用于生产重组蛋白的细胞中也存在的非内源DNA的表达产生的。

8. 发明授权

US5599904A Chimeric steroid hormone superfamily receptor proteins 失效
标题翻译：嵌合类固醇激素超家族受体蛋白
公开(公告)号：US5599904A
公开(公告)日：1997-02-04
申请号：US845857
申请日：1992-03-03
申请人： Ronald M. Evans , Estelita S. Ong , Prudimar S. Segui , Catherine C. Thompson , Kazuhiko Umesono , Vincent Giguere
发明人： Ronald M. Evans , Estelita S. Ong , Prudimar S. Segui , Catherine C. Thompson , Kazuhiko Umesono , Vincent Giguere
IPC分类号： C12N15/09 , C07K14/435 , C07K14/705 , C07K14/72 , C07K19/00 , C12N5/00 , C12N5/10 , C12N15/00 , C12N15/12 , C12P21/02 , C12Q1/68 , C12R1/91 , G01N33/15 , G01N33/50 , G01N33/566
CPC分类号： C12Q1/6897 , C07K14/70567 , C07K2319/00 , C07K2319/61 , C07K2319/715 , C07K2319/81
摘要： A novel retinoic acid receptor is disclosed. The novel receptor is encoded for by cDNA carried on plasmid phRAR1, which has been deposited with the American Type Culture Collection for patent purposes. Chimeric receptor proteins are also disclosed. The chimera are constructed by exchanging functional domains between the glucocorticoid, the mineralocorticoid, the estrogen-related, the thyroid and the retinoic acid receptors. In addition, a novel method for identifying functional ligands for receptor proteins is disclosed. The method, which takes advantage of the modular structure of the hormone receptors and the idea that the functional domains may be interchangeable, replaces the DNA-binding domain of a putative novel receptor with the DNA-binding domain of a known receptor such as the glucocorticoid receptor. The resulting chimeric construction, when expressed in cells, produces a hybrid receptor whose activation of a ligand-(e.g., glucocorticoid) inducible promoter is dependent on the presence of the new ligand. The novel method is illustrated in part by showing that the ligand for the new receptor protein is the retinoid, retinoic acid.
摘要翻译：公开了一种新型视黄酸受体。新型受体由携带在质粒phRAR1上的cDNA编码，其已经保藏在美国典型培养物保藏中心用于专利。还公开了嵌合受体蛋白。通过在糖皮质激素，盐皮质激素，雌激素相关，甲状腺和视黄酸受体之间交换功能结构来构建嵌合体。另外，公开了用于鉴定受体蛋白质的功能性配体的新方法。利用激素受体的模块化结构的方法和功能域可以互换的想法将已知受体的DNA结合结构域（例如糖皮质激素）替代推定的新受体的DNA结合结构域受体。当在细胞中表达时，产生的嵌合构型产生杂合受体，其配体（例如，糖皮质激素）诱导型启动子的活化取决于新配体的存在。该新方法部分地通过显示新受体蛋白质的配体是类视黄醇，视黄酸来说明。

9. 发明授权

US5571692A Retinoic acid receptor .alpha., vectors and cells comprising the same DNA encoding 失效
标题翻译：视黄酸受体α，载体和包含编码相同DNA的细胞
公开(公告)号：US5571692A
公开(公告)日：1996-11-05
申请号：US168686
申请日：1993-12-16
申请人： Ronald M. Evans , Estelita S. Ong , Prudimar S. Segui , Catherine C. Thompson , Kazuhiko Umesono , Vincent Giguere
发明人： Ronald M. Evans , Estelita S. Ong , Prudimar S. Segui , Catherine C. Thompson , Kazuhiko Umesono , Vincent Giguere
IPC分类号： C07K14/705 , C12Q1/68 , C12N15/12 , C12N1/21 , C12N5/10 , C12N15/63
CPC分类号： C12Q1/6897 , C07K14/70567 , C07K2319/00 , C07K2319/61 , C07K2319/715 , C07K2319/81
摘要： DNA encoding a human retinoic acid receptor alpha protein is disclosed. The sequence of the receptor is encoded by the cDNA insert of plasmid phRAR1, which has been deposited with ATCC. Methods employing chimeric receptors derived from the retinoic acid receptor are illustrated which demonstrate that the ligand for the new receptor is the retinoid, retinoic acid.
摘要翻译：公开了编码人视黄酸受体α蛋白的DNA。受体的序列由已经保藏于ATCC的质粒phRAR1的cDNA插入片段编码。示出了使用衍生自视黄酸受体的嵌合受体的方法，其表明新受体的配体是类视黄醇维甲酸。

10. 发明授权

US5171671A Retinoic acid receptor composition 失效
标题翻译：视黄酸受体组成
公开(公告)号：US5171671A
公开(公告)日：1992-12-15
申请号：US546256
申请日：1990-08-06
申请人： Ronald M. Evans , Estelita S. Ong , Prudimar S. Segui , Catherine C. Thompson , Kazuhiko Uemsono , Vincent Giguere
发明人： Ronald M. Evans , Estelita S. Ong , Prudimar S. Segui , Catherine C. Thompson , Kazuhiko Uemsono , Vincent Giguere
IPC分类号： C07K14/705 , C12N15/12 , C12N15/62 , C12Q1/68
CPC分类号： C07K14/70567 , C12N15/62 , C12Q1/6897 , C07K2319/00 , C07K2319/61 , C07K2319/715 , C07K2319/81
摘要： A novel retinoic acid receptor is disclosed. The novel receptor is encoded for by cDNA carried on plasmid phRAR1, which has been deposited with the American Type Culture Collection for patent purposes. Chimeric receptor proteins are also disclosed. The chimera are constructed by exchanging functional domains between the glucocorticoid, the mineralocorticoid, the estrogen-related, the thyroid and the retinoic acid receptors. In addition, a novel method for identifying functional ligands for receptor proteins is disclosed. The method, which takes advantage of the modular structure of the hormone receptors and the idea that the functional domains may be interchangeable, replaces the DNA-binding domain of a putative novel receptor with the DNA-binding domain of a known receptor such as the glucocorticoid receptor. The resulting chimeric construction, when expressed in cells, produces a hybrid receptor whose activation of a ligand-(e.g., glucocorticoid) inducible promoter is dependent on the presence of the new ligand. The novel method is illustrated in part by showing that the ligand for the new receptor protein is the retinoid, retinoic acid.
摘要翻译：公开了一种新型视黄酸受体。新型受体由携带在质粒phRAR1上的cDNA编码，其已经保藏在美国典型培养物保藏中心用于专利。还公开了嵌合受体蛋白。通过在糖皮质激素，盐皮质激素，雌激素相关，甲状腺和视黄酸受体之间交换功能结构来构建嵌合体。另外，公开了用于鉴定受体蛋白质的功能性配体的新方法。利用激素受体的模块化结构的方法和功能域可以互换的想法将已知受体的DNA结合结构域（例如糖皮质激素）替代推定的新受体的DNA结合结构域受体。当在细胞中表达时，产生的嵌合构型产生杂合受体，其配体（例如，糖皮质激素）诱导型启动子的活化取决于新配体的存在。该新方法部分地通过显示新受体蛋白质的配体是类视黄醇，视黄酸来说明。

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