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1. 发明授权

US06391572B1 Methods for identifying modulators of transcriptional activator protein interactions 失效
标题翻译：用于鉴定转录激活蛋白相互作用的调节剂的方法
公开(公告)号：US06391572B1
公开(公告)日：2002-05-21
申请号：US09387418
申请日：1999-08-31
申请人： Xiaokui Zhang , Curt Horvath , Melissa H. Wrzeszczynska , James E. Darnell, Jr.
发明人： Xiaokui Zhang , Curt Horvath , Melissa H. Wrzeszczynska , James E. Darnell, Jr.
IPC分类号： G01N3353
CPC分类号： C07K14/4705 , C07K2319/00 , G01N33/5008 , G01N33/5011 , G01N33/5017 , G01N33/502 , G01N33/68 , G01N33/6845 , G01N2333/4715
摘要： The present invention relates to methods for identifying interacting regions of transcription factors, and methods for identifying agents which modulate the interactions, useful for affecting gene regulation, for example, cellular transformation. A site within residues 130-154 and within residues 343-358 in Stat3 were found to interact with the transcription factor c-Jun. On c-Jun, a site within residues 105 and 334, and more particularly, between 105 and 263, interact with Stat3. These sites of interactions permit methods for identifying agents which modulate the interaction between these transcription factors to modulate gene transcription.
摘要翻译：本发明涉及用于鉴定转录因子的相互作用区域的方法，以及用于鉴定调节相互作用的试剂的方法，其用于影响基因调控，例如细胞转化。发现Stat3中残基130-154和343-358位残基内的位点与转录因子c-Jun相互作用。在c-Jun上，残基105和334内的位点，特别是105和263之间的位点与Stat3相互作用。这些相互作用的位点允许用于鉴定调节这些转录因子之间的相互作用以调节基因转录的试剂的方法。

2. 发明授权

US06960647B2 Stat3 protein fragments and mutants 失效
标题翻译： Stat3蛋白片段和突变体
公开(公告)号：US06960647B2
公开(公告)日：2005-11-01
申请号：US10090185
申请日：2002-03-04
申请人： Xiaokui Zhang , Curt Horvath , Melissa H. Wrzeszczynska , James E. Darnell, Jr.
发明人： Xiaokui Zhang , Curt Horvath , Melissa H. Wrzeszczynska , James E. Darnell, Jr.
IPC分类号： C07K14/47 , G01N33/68
CPC分类号： C07K14/4705 , C07K2319/00 , G01N33/5008 , G01N33/5011 , G01N33/5017 , G01N33/502 , G01N33/68 , G01N33/6845 , G01N2333/4715
摘要： The present invention relates to methods for identifying interacting regions of transcription factors, and methods for identifying agents which modulate the interactions, useful for affecting gene regulation, for example, cellular transformation. A site within residues 130-154 and within residues 343-358 in Stat3 were found to interact with the transcription factor c-Jun. On c-Jun, a site within residues 105 and 334, and more particularly, between 105 and 263, interact with Stat3. These sites of interactions permit methods for identifying agents which modulate the interaction between these transcription factors to modulate gene transcription.
摘要翻译：本发明涉及用于鉴定转录因子的相互作用区域的方法，以及用于鉴定调节相互作用的试剂的方法，其用于影响基因调控，例如细胞转化。发现Stat3中残基130-154和343-358位残基内的位点与转录因子c-Jun相互作用。在c-Jun上，残基105和334内的位点，特别是105和263之间的位点与Stat3相互作用。这些相互作用的位点允许用于鉴定调节这些转录因子之间的相互作用以调节基因转录的试剂的方法。

3. 发明授权

US07211655B2 Methods for identifying modulators of transcriptional activator protein interactions 失效
标题翻译：用于鉴定转录激活蛋白相互作用的调节剂的方法
公开(公告)号：US07211655B2
公开(公告)日：2007-05-01
申请号：US11218272
申请日：2005-09-01
申请人： Xiaokui Zhang , Curt Horvath , Melissa H. Wrzeszczynska , James E. Darnell, Jr.
发明人： Xiaokui Zhang , Curt Horvath , Melissa H. Wrzeszczynska , James E. Darnell, Jr.
IPC分类号： C07H21/02 , C07K14/00 , C12N15/63
CPC分类号： C07K14/4705 , C07K2319/00 , G01N33/5008 , G01N33/5011 , G01N33/5017 , G01N33/502 , G01N33/68 , G01N33/6845 , G01N2333/4715
摘要： The present invention relates to methods for identifying interacting regions of transcription factors, and methods for identifying agents which modulate the interactions, useful for affecting gene regulation, for example, cellular transformation. A site within residues 130–154 and within residues 343–358 in Stat3 were found to interact with the transcription factor c-Jun. On c-Jun, a site within residues 105 and 334, and more particularly, between 105 and 263, interact with Stat3. These sites of interactions permit methods for identifying agents which modulate the interaction between these transcription factors to modulate gene transcription.
摘要翻译：本发明涉及用于鉴定转录因子的相互作用区域的方法，以及用于鉴定调节相互作用的试剂的方法，其用于影响基因调控，例如细胞转化。发现Stat3中残基130-154和343-358位残基内的位点与转录因子c-Jun相互作用。在c-Jun上，残基105和334内的位点，特别是105和263之间的位点与Stat3相互作用。这些相互作用的位点允许用于鉴定调节这些转录因子之间的相互作用以调节基因转录的试剂的方法。

4. 发明授权

US06235873B1 Constitutively active transcription factors and their uses for identifying modulators of activity including dysproliferative cellular changes 失效
标题翻译：组成型活性转录因子及其用于鉴定活化调节因子的用途，包括增生性增殖细胞变化
公开(公告)号：US06235873B1
公开(公告)日：2001-05-22
申请号：US09364970
申请日：1999-07-31
申请人： Jacqueline F. Bromberg , Melissa H. Wrzeszczynska , Yanxiang Zhao , James E. Darnell, Jr.
发明人： Jacqueline F. Bromberg , Melissa H. Wrzeszczynska , Yanxiang Zhao , James E. Darnell, Jr.
IPC分类号： A61K3800
CPC分类号： C07K14/4705 , C07K2319/00
摘要： The invention is directed to constitutively active Stat proteins and methods for their preparation. The modified Stat proteins have at least one cysteine residue which may interact with the corresponding cysteine residue on another modified Stat protein to form a dimer. The constitutively active Stat proteins are capable of binding to DNA and activating transcription in the absence of tyrosine phosphorylation. Cell lines expressing the modified Stat protein exhibit a transformed phenotype and are capable of forming tumors in nude mice. Methods are describe utilizing the modified Stat proteins of the invention in the absence and presence of tyrosine phosphorylation in identifying agents capable of modulating Stat protein dimerization, transcriptional activity, and cellular transformation in vitro and in vivo. The invention is also directed to polynucleotides encoding modified, constitutively active Stat proteins.
摘要翻译：本发明涉及组成型活性Stat蛋白及其制备方法。修饰的Stat蛋白具有至少一个半胱氨酸残基，其可与另一修饰的Stat蛋白上的相应半胱氨酸残基相互作用以形成二聚体。组成型活性的Stat蛋白能够在不存在酪氨酸磷酸化的情况下结合DNA并激活转录。表达经修饰的Stat蛋白的细胞系表现出转化的表型并且能够在裸小鼠中形成肿瘤。描述了在确定能够在体外和体内调节Stat蛋白二聚化，转录活性和细胞转化的鉴定试剂中，在不存在和存在酪氨酸磷酸化的情况下利用本发明的经修饰的Stat蛋白的方法。本发明还涉及编码修饰的，组成型活性的Stat蛋白的多核苷酸。

5. 发明授权

US07417120B2 Purified Stat proteins and methods of purifying thereof 失效
标题翻译：纯化的Stat蛋白及其纯化方法
公开(公告)号：US07417120B2
公开(公告)日：2008-08-26
申请号：US11335005
申请日：2006-01-19
申请人： Uwe Vinkemeier , James E. Darnell, Jr.
发明人： Uwe Vinkemeier , James E. Darnell, Jr.
IPC分类号： C07K1/00
CPC分类号： B01J20/26 , B01D15/166 , B01D15/3804 , B01J20/262 , B01J20/265 , B01J20/285 , B01J20/3242 , C07K14/4702 , C07K14/4705 , C12N2799/026 , G01N33/6872 , G01N2333/4706 , G01N2500/02
摘要： The present invention describes methods of producing milligram quantities of three forms of purified Stat1 protein from recombinant DNA constructs. In addition, the Stat proteins may be isolated in their phosphorylated or nonphosphorylated forms (Tyr 701). The proteins can be produced in baculovirus infected insect cells, or E. coli. A compact domain in the amino terminus of Stat1α was isolated and found to enhance DNA binding due to its ability to interact with a neighboring Stat protein. A relatively protease-resistant recombinant truncated form of the Stat protein was isolated in 40-50 mg quantities. Purification of the Stat proteins were performed after modifying specific cysteine residues of the Stat proteins to prevent aggregation. Activated EGF-receptor partially purified from membranes by immunoprecipitation was shown to be capable of in vitro catalysis of the phosphorylation of the tyrosine residue of Stat1 known to be phosphorylated in vivo. Techniques are enclosed to separate the phosphorylated from the nonphosphorylated Stat proteins. The techniques disclosed are general for Stat proteins and may be used to isolate large quantities of purified Stat 2, 3, 4, 5A, 5B and 6. Methods for using purified Stat proteins, truncated Stat proteins, or Stat N-terminal fragments for drug discovery are also disclosed.
摘要翻译：本发明描述了从重组DNA构建体产生毫克量的三种形式的纯化的Stat1蛋白的方法。此外，Stat蛋白可以以其磷酸化或非磷酸化形式（Tyr 701）分离。蛋白质可以在杆状病毒感染的昆虫细胞或大肠杆菌中产生。分离Stat1alpha氨基末端的紧密结构域，由于其与邻近Stat蛋白质相互作用的能力，发现DNA结合增强。以40-50mg的量分离相对蛋白酶的重组截短形式的Stat蛋白。 Stat蛋白的纯化在Stat蛋白的特异性半胱氨酸残基修饰后进行，以防止聚集。通过免疫沉淀从膜部分纯化的活化的EGF受体显示能够体外催化已知在体内被磷酸化的Stat1的酪氨酸残基的磷酸化。封闭技术以将磷酸化的非磷酸化Stat蛋白分离。所公开的技术对于Stat蛋白是普遍的，并且可以用于分离大量纯化的Stat2,3,4,5A，5B和6.使用纯化的Stat蛋白，截短的Stat蛋白或Stat N末端片段进行药物的方法发现也被披露。

6. 发明授权

US07339039B2 Nucleic acids encoding receptor recognition factors, and methods of use thereof 失效
标题翻译：编码受体识别因子的核酸及其使用方法
公开(公告)号：US07339039B2
公开(公告)日：2008-03-04
申请号：US09876773
申请日：2001-06-07
申请人： James E. Darnell, Jr. , Christian W. Schindler , Xin-Yuan Fu , Zilong Wen , Zhong Zhong
发明人： James E. Darnell, Jr. , Christian W. Schindler , Xin-Yuan Fu , Zilong Wen , Zhong Zhong
IPC分类号： C07H21/04 , C12P21/06 , C07K14/00
CPC分类号： C12N15/113 , A61K38/21 , C07K14/4705 , Y02A50/473 , A61K2300/00
摘要： Receptor recognition factors exist that recognizes the specific cell receptor to which a specific ligand has been bound, and that may thereby signal and/or initiate the binding of the transcription factor to the DNA site. The receptor recognition factor is in one instance, a part of a transcription factor, and also may interact with other transcription factors to cause them to activate and travel to the nucleus for DNA binding. The receptor recognition factor appears to be second-messenger-independent in its activity, as overt perturbations in second messenger concentrations are of no effect. The concept of the invention is illustrated by the results of studies conducted With interferon (IFN)-stimulated gene transcription, and particularly, the activation caused by both IFNα and IFNγ. Specific DNA and amino acid sequences for various human and murine receptor recognition factors are provided, as are polypeptide fragments of two of the ISGF-3 genes, and antibodies have also been prepared and tested. The polypeptides confirm direct involvement of tyrosine kinase in intracellular message transmission. Numerous diagnostic and therapeutic materials and utilities are also disclosed.
摘要翻译：存在识别特异性配体已被结合的特异性细胞受体的受体识别因子，从而可以将转录因子与DNA位点的结合信号和/或启动。受体识别因子在一个例子中是转录因子的一部分，并且还可以与其他转录因子相互作用，以使其激活并前往细胞核进行DNA结合。受体识别因子似乎在其活动中是与第二信使无关的，因为第二信使浓度的明显的扰动是无效的。通过用干扰素（IFN）刺激的基因转录，特别是由IFNα和IFNγ引起的活化的研究结果说明了本发明的概念。提供了各种人和鼠受体识别因子的特异性DNA和氨基酸序列，两种ISGF-3基因的多肽片段也已经被制备和测试。这些多肽证实了酪氨酸激酶在细胞内消息传播中的直接参与。还公开了许多诊断和治疗材料和效用。

7. 发明授权

US6030808A Nucleic acids encoding receptor recognition factor stat 3 and methods of use thereof 失效
标题翻译：编码受体识别因子stat 3的核酸及其使用方法
公开(公告)号：US6030808A
公开(公告)日：2000-02-29
申请号：US956869
申请日：1997-10-23
申请人： James E. Darnell, Jr. , Christian W. Schindler , Xin-Yuan Fu , Zilong Wen , Zhong Zhong
发明人： James E. Darnell, Jr. , Christian W. Schindler , Xin-Yuan Fu , Zilong Wen , Zhong Zhong
IPC分类号： A61K38/00 , A61K38/21 , C07K14/47 , C07K16/28 , C12N15/113 , C12N15/12 , C12P21/08 , C12Q1/68 , G01N33/53 , G01N33/567 , C07H21/04 , C12N15/63
CPC分类号： C12N15/113 , A61K38/21 , C07K14/4705
摘要： Receptor recognition factors exist that recognizes the specific cell receptor to which a specific ligand has been bound, and that may thereby signal and/or initiate the binding of the transcription factor to the DNA site. The receptor recognition factor is in one instance, a part of a transcription factor, and also may interact with other transcription factors to cause them to activate and travel to the nucleus for DNA binding. The receptor recognition factor appears to be second-messenger-independent in its activity, as overt perturbations in second messenger concentrations are of no effect. The concept of the invention is illustrated by the results of studies conducted with interferon (IFN)-stimulated gene transcription, and particularly, the activation caused by both IFN.alpha. and IFN-.gamma.. Specific DNA and amino acid sequences for various human and murine receptor recognition factors are provided, as are polypeptide fragments of two of the ISGF-3 genes, and antibodies have also been prepared and tested. The polypeptides confirm direct involvement of tyrosine kinase in intracellular message transmission. Numerous diagnostic and therapeutic materials and utilities are also disclosed.
摘要翻译：存在识别特异性配体已被结合的特异性细胞受体的受体识别因子，从而可以将转录因子与DNA位点的结合信号和/或启动。受体识别因子在一个例子中是转录因子的一部分，并且还可以与其他转录因子相互作用，以使其激活并前往细胞核进行DNA结合。受体识别因子似乎在其活动中是与第二信使无关的，因为第二信使浓度的明显的扰动是无效的。通过用干扰素（IFN）刺激的基因转录进行的研究结果，特别是由IFNα和IFN-γ引起的活化来说明本发明的概念。提供了各种人和鼠受体识别因子的特异性DNA和氨基酸序列，两种ISGF-3基因的多肽片段也已经被制备和测试。这些多肽证实了酪氨酸激酶在细胞内消息传播中的直接参与。还公开了许多诊断和治疗材料和效用。

8. 发明授权

US06605442B1 Methods of testing drugs or agents that modulate the activity of receptor recognition factors 失效
标题翻译：测试调节受体识别因子活性的药物或药剂的方法
公开(公告)号：US06605442B1
公开(公告)日：2003-08-12
申请号：US08212185
申请日：1994-03-11
申请人： James E. Darnell, Jr. , Christian W. Schindler , Xin-Yuan Fu , Zilong Wen , Zhong Zhong
发明人： James E. Darnell, Jr. , Christian W. Schindler , Xin-Yuan Fu , Zilong Wen , Zhong Zhong
IPC分类号： G01N3353
CPC分类号： C12N15/113 , A61K38/21 , C07K14/4705 , Y02A50/473 , A61K2300/00
摘要： Receptor recognition factors exist that recognizes the specific cell receptor to which a specific ligand has been bound, and that may thereby signal and/or initiate the binding of the transcription factor to the DNA site. The receptor recognition factor is in one instance, a part of a transcription factor, and also may interact with other transcription factors to cause them to activate and travel to the nucleus for DNA binding. The receptor recognition factor appears to be second-messenger-independent in its activity, as overt perturbations in second messenger concentrations are of no effect. The concept of the invention is illustrated by the results of studies conducted with interferon (IFN)-stimulated gene transcription, and particularly, the activation caused by both IFN&agr; and IFN&ggr;. Specific DNA and amino acid sequences for various human and murine receptor recognition factors are provided, as are polypeptide fragments of two of the ISGF-3 genes, and antibodies have also been prepared and tested. The polypeptides confirm direct involvement of tyrosine kinase in intracellular message transmission. Numerous diagnostic and therapeutic materials and utilities are also disclosed.
摘要翻译：存在识别特异性配体已被结合的特异性细胞受体的受体识别因子，从而可以将转录因子与DNA位点的结合信号和/或启动。受体识别因子在一个例子中是转录因子的一部分，并且还可以与其他转录因子相互作用，以使其激活并前往细胞核进行DNA结合。受体识别因子似乎在其活动中是与第二信使无关的，因为第二信使浓度的明显的扰动是无效的。通过用干扰素（IFN）刺激的基因转录进行的研究结果，特别是由IFNα和IFNγ引起的活化来说明本发明的概念。提供了各种人和鼠受体识别因子的特异性DNA和氨基酸序列，两种ISGF-3基因的多肽片段也已经被制备和测试。这些多肽证实了酪氨酸激酶在细胞内消息传播中的直接参与。还公开了许多诊断和治疗材料和效用。

9. 发明授权

US6013475A Nucleic acids encoding receptor recognition factors and methods of use thereof 失效
标题翻译：编码受体识别因子的核酸及其使用方法
公开(公告)号：US6013475A
公开(公告)日：2000-01-11
申请号：US956652
申请日：1997-10-23
申请人： James E. Darnell, Jr. , Christian W. Schindler , Xin-Yuan Fu , Zilong Wen , Zhong Zhong
发明人： James E. Darnell, Jr. , Christian W. Schindler , Xin-Yuan Fu , Zilong Wen , Zhong Zhong
IPC分类号： A61K38/00 , A61K38/21 , C07K14/47 , C07K16/28 , C12N15/113 , C12N15/12 , C12P21/08 , C12Q1/68 , G01N33/53 , G01N33/567
CPC分类号： C12N15/113 , A61K38/21 , C07K14/4705
摘要： Receptor recognition factors exist that recognizes the specific cell receptor to which a specific ligand has been bound, and that may thereby signal and/or initiate the binding of the transcription factor to the DNA site. The receptor recognition factor is in one instance, a part of a transcription factor, and also may interact with other transcription factors to cause them to activate and travel to the nucleus for DNA binding. The receptor recognition factor appears to be second-messenger-independent in its activity, as overt perturbations in second messenger concentrations are of no effect. The concept of the invention is illustrated by the results of studies conducted with interferon (IFN)-stimulated gene transcription, and particularly, the activation caused by both IFN.alpha. and IFN.gamma.. Specific DNA and amino acid sequences for various human and murine receptor recognition factors are provided, as are polypeptide fragments of two of the ISGF-3 genes, and antibodies have also been prepared and tested. The polypeptides confirm direct involvement of tyrosine kinase in intracellular message transmission. Numerous diagnostic and therapeutic materials and utilities are also disclosed.
摘要翻译：存在识别特异性配体已被结合的特异性细胞受体的受体识别因子，从而可以将转录因子与DNA位点的结合信号和/或启动。受体识别因子在一个例子中是转录因子的一部分，并且还可以与其他转录因子相互作用，以使其激活并前往细胞核进行DNA结合。受体识别因子似乎在其活动中是与第二信使无关的，因为第二信使浓度的明显的扰动是无效的。通过用干扰素（IFN）刺激的基因转录进行的研究结果，特别是由IFNα和IFNγ引起的活化来说明本发明的概念。提供了各种人和鼠受体识别因子的特异性DNA和氨基酸序列，两种ISGF-3基因的多肽片段也已经被制备和测试。这些多肽证实了酪氨酸激酶在细胞内消息传播中的直接参与。还公开了许多诊断和治疗材料和效用。

10. 发明授权

US5883228A Functionally active regions of signal transducer and activator of transcription 失效
标题翻译：信号传感器和转录激活子的功能活跃区域
公开(公告)号：US5883228A
公开(公告)日：1999-03-16
申请号：US852091
申请日：1997-05-06
申请人： James E. Darnell, Jr. , Zilong Wen , Curt M. Horvath , Zhong Zhong
发明人： James E. Darnell, Jr. , Zilong Wen , Curt M. Horvath , Zhong Zhong
IPC分类号： A61K38/00 , A61K48/00 , C07K14/47 , C07K1/00 , A61K38/17
CPC分类号： C07K14/4718 , C07K14/4705 , A61K38/00 , A61K48/00 , Y10S530/81 , Y10S530/827
摘要： The present invention relates generally to intracellular receptor recognition proteins or factors, termed Signal Transducers and Activators of Transcription (STAT), to methods and compositions utilizing such factors, and to the antibodies reactive toward them, in assays and for diagnosing, preventing and/or treating cellular debilitation, derangement or dysfunction. More particularly, the present invention relates to particular functional domains of molecules that exhibit both receptor recognition and message delivery via DNA binding in receptor-ligand specific manner, i.e., that directly participate both in the interaction with the ligand-bound receptor at the cell surface and in the activity of transcription in the nucleus as a DNA binding protein. The invention likewise relates to the antibodies and other entities that are specific to the functional domain of a STAT protein and that would thereby selectively modulate its activity.
摘要翻译：本发明一般涉及称为信号转导和转录激活因子（STAT）的细胞内受体识别蛋白或因子，涉及利用这些因子的方法和组合物，以及在测定中用于诊断，预防和/或治疗细胞衰弱，紊乱或功能障碍。更具体地说，本发明涉及通过受体 - 配体特异性方式的DNA结合表现出受体识别和消息传递的分子的特定功能结构域，即直接参与与细胞表面的配体结合受体的相互作用并且在细胞核中作为DNA结合蛋白的转录活性。本发明同样涉及对STAT蛋白的功能结构域特异的抗体和其它实体，从而选择性调节其活性。

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