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1. 发明申请

WO0011195A9 C-MYC IS ACTIVATED BY BETA-CATENIN AND TCF-4 审中-公开
标题翻译： C-MYC是由卡培他滨和TCF-4激活的
公开(公告)号：WO0011195A9
公开(公告)日：2002-08-22
申请号：PCT/US9918774
申请日：1999-08-20
申请人： UNIV JOHNS HOPKINS MED , HE TONG-CHUAN , VOGELSTEIN BERT , KINZLER KENNETH W
发明人： HE TONG-CHUAN , VOGELSTEIN BERT , KINZLER KENNETH W
IPC分类号： C12N15/09 , A61K31/711 , A61K38/00 , A61K45/00 , A61K48/00 , A61P35/00 , C07K14/47 , C12N15/12 , C12Q1/02 , C12Q1/68 , G01N33/15 , G01N33/50 , C12N15/63 , C07K14/27
CPC分类号： C07K14/47 , A61K38/00 , A61K48/00 , C07K14/4705 , C12Q1/6897
摘要： The APC tumor suppressor protein binds to beta -catenin, a protein recently shown to interact with Tcf/Lef transcription factors. Here, the gene encoding a Tcf family member that is expressed in colonic epithelium (hTcf-4) was cloned and characterized. hTcf-4 transactivates transcription only when associated with beta -catenin. Nuclei of APC colon carcinoma cells were found to contain a stable beta -catenin-hTCF-4 complex that was constitutively active, as measured by transcription of a Tcf reporter gene. Reintroduction of APC removed beta -catenin from hTcf4 and abrogated the transcriptional transactivation. Constitutive transcription of TCF target genes, caused by loss of APC function, may be a crucial event in the early transformation of colonic epithelium. It is also shown here that the products of mutant APC genes found in colorectal tumors are defective in regulating beta -catenin/Tcf-4 transcriptional activation. Furthermore, colorectal tumors with intact APC genes were shown to contain subtle activating mutations of beta -catenin that altered functionally significant phosphorylation sites. These results indicate that regulation of beta -catenin is critical to APC's tumor suppressive effect and that this regulation can be circumvented by mutations in either APC or beta -catenin.
摘要翻译： APC肿瘤抑制蛋白结合β-连环蛋白，最近显示出与Tcf / Lef转录因子相互作用的蛋白质。这里，克隆并表征编码在结肠上皮（hTcf-4）中表达的Tcf家族成员的基因。 hTcf-4仅在与β-连环蛋白相关时才转录转录。发现APC < - / - >结肠癌细胞的核含有一个稳定的β-连环蛋白-hTCF-4复合物，其通过Tcf报告基因的转录测量而具有组成型活性。重新引入APC从hTcf4中除去β-连环蛋白，并废除转录反式激活。由APC功能丧失引起的TCF靶基因的组成转录可能是结肠上皮早期转化的关键事件。这里还显示，在结肠直肠肿瘤中发现的突变APC基因的产物在调节β-连环蛋白/ Tcf-4转录激活中是缺陷的。此外，具有完整APC基因的结肠直肠肿瘤显示含有改变功能显着磷酸化位点的β-连环蛋白的微妙活化突变。这些结果表明，β-连环蛋白的调节对于APC的肿瘤抑制作用至关重要，并且该调节可以通过APC或β-连环蛋白的突变来规避。

2. 发明申请

WO0116167A3 BETA-CATENIN, TCF-4, AND APC INTERACT TO PREVENT CANCER 审中-公开
标题翻译： BETA-CATENIN，TCF-4和APC相互作用以预防癌症
公开(公告)号：WO0116167A3
公开(公告)日：2001-09-20
申请号：PCT/US0023635
申请日：2000-08-29
申请人： UNIV JOHNS HOPKINS , BARKER NICHOLAS , CLEVERS JOHANNES C , KINZLER KENNETH W , KORINEK VLADIMIR , MORIN PATRICE J , SPARKS ANDREW B , VOGELSTEIN BERT , HE TONG CHUAN
发明人： BARKER NICHOLAS , CLEVERS JOHANNES C , KINZLER KENNETH W , KORINEK VLADIMIR , MORIN PATRICE J , SPARKS ANDREW B , VOGELSTEIN BERT , HE TONG-CHUAN
IPC分类号： A61K38/00 , A61K48/00 , C07K14/47 , A61K38/17 , A61P35/00 , C12N15/12 , C12N15/62
CPC分类号： C07K14/47 , A61K38/00 , A61K48/00 , C07K2319/00 , C12N2799/022
摘要： A recombinant adenovirus (Ad-Mini-ME) which constitutively expresses the central third of APC includes all of the known beta -catenin binding repeats. When expressed in colon cancer cells, Ad-Mini-ME blocked the nuclear translocation of beta -catenin and inhibited beta -catenin/Tcf-4-mediated transactivation. Accordingly, expression of endogenous targets of the APC/ beta -catenin/Tcf-4 pathway were down-regulated. Ad-Mini-ME infection of colorectal cancer cell lines with mutant APC but wild-type beta -catenin resulted in substantial growth arrest followed by apoptosis. These findings suggest that the beta -catenin binding domain in the central third of APC is sufficient for its tumor suppresion activity.
摘要翻译：组成型表达APC中心三分之一的重组腺病毒（Ad-Mini-ME）包括所有已知的β-连环蛋白结合重复序列。当在结肠癌细胞中表达时，Ad-Mini-ME阻断β-连环蛋白的核转位并抑制β-连环蛋白/ Tcf-4介导的反式激活。因此，APC /β-连环蛋白/ Tcf-4途径的内源靶标的表达下调。具有突变型APC但具有野生型β-连环蛋白的结肠直肠癌细胞系的Ad-Mini-ME感染导致大量生长停滞，随后凋亡。这些研究结果表明APC中央三分之一的β-连环蛋白结合结构域对于其肿瘤抑制活性是足够的。

3. 发明申请

WO0070089A9 CDX2 IS DOWNSTREAM MEDIATOR OF APC TUMOR SUPPRESSOR ACTIVITY 审中-公开
标题翻译： CDX2是APC肿瘤抑制剂活性的下调介质
公开(公告)号：WO0070089A9
公开(公告)日：2001-11-22
申请号：PCT/US0012893
申请日：2000-05-12
申请人： UNIV JOHNS HOPKINS , DACOSTA LUIS , VOGELSTEIN BERT , KINZLER KENNETH W , HE TONG CHUAN
发明人： DACOSTA LUIS , VOGELSTEIN BERT , KINZLER KENNETH W , HE TONG-CHUAN
IPC分类号： C07K14/47 , C07K14/705 , C12N5/08 , C12Q1/68
CPC分类号： C07K14/4702 , C07K14/705 , C12Q1/6897
摘要： Human CDX2, a homeobox gene, has been identified as a downstream effector of tumor suppressor APC. APC induces the transcription of CDX2. This newly found relationship permits specific drug screening assays as well as therapeutic and diagnostic methods.
摘要翻译：人CDX2是同源盒基因，已被鉴定为肿瘤抑制因子APC的下游效应物。 APC诱导CDX2的转录。这种新发现的关系允许特定的药物筛选测定以及治疗和诊断方法。

4. 发明专利

AT362989T 未知
公开(公告)号：AT362989T
公开(公告)日：2007-06-15
申请号：AT99908441
申请日：1999-02-25
申请人： UNIV JOHNS HOPKINS MED
发明人： HE TONG-CHUAN , VOGELSTEIN BERT , KINZLER KENNETH
IPC分类号： C12N15/86 , C07K14/075 , C12N5/10 , C12N7/00 , C12N15/00 , C12N15/861 , C12R1/01
摘要： Recombinant adenoviruses provide a versatile system for gene expression studies and therapeutic applications. This invention describes a strategy which simplifies the generation and production of such viruses. A recombinant adenoviral plasmid is generated with a minimum of enzymatic manipulations, employing homologous recombination in bacteria rather than in eucaryotic cells. Following transfections of such plasmids into a mammalian packaging cell line, viral production can be conveniently followed with the aid of green fluorescent protein, encoded by a gene incorporated into the viral backbone. Homogeneous viruses can be obtained from this procedure without plaque purification. This system expedites the process of generating and testing recombinant adenoviruses.

5. 发明专利

DE69917649D1 未知
公开(公告)号：DE69917649D1
公开(公告)日：2004-07-01
申请号：DE69917649
申请日：1999-08-20
申请人： UNIV JOHNS HOPKINS MED
发明人： HE TONG-CHUAN , VOGELSTEIN BERT , KINZLER W
IPC分类号： C12N15/09 , A61K31/711 , A61K38/00 , A61K45/00 , A61K48/00 , A61P35/00 , C07K14/47 , C12N15/12 , C12Q1/02 , C12Q1/68 , C12Q1/6897 , G01N33/15 , G01N33/50 , C12N15/63 , C07K14/27
摘要： The APC tumor suppressor protein binds to beta -catenin, a protein recently shown to interact with Tcf/Lef transcription factors. Here, the gene encoding a Tcf family member that is expressed in colonic epithelium (hTcf-4) was cloned and characterized. hTcf-4 transactivates transcription only when associated with beta -catenin. Nuclei of APC-/- colon carcinoma cells were found to contain a stable beta -catenin-hTCF-4 complex that was constitutively active, as measured by transcription of a Tcf reporter gene. Reintroduction of APC removed beta -catenin from hTcf4 and abrogated the transcriptional transactivation. Constitutive transcription of TCF target genes, caused by loss of APC function, may be a crucial event in the early transformation of colonic epithelium. It is also shown here that the products of mutant APC genes found in colorectal tumors are defective in regulating beta -catenin/Tcf-4 transcriptional activation. Furthermore, colorectal tumors with intact APC genes were shown to contain subtle activating mutations of beta -catenin that altered functionally significant phosphorylation sites. These results indicate that regulation of beta -catenin is critical to APC's tumor suppressive effect and that this regulation can be circumvented by mutations in either APC or beta -catenin.

6. 发明专利

DE69936134D1 未知
公开(公告)号：DE69936134D1
公开(公告)日：2007-07-05
申请号：DE69936134
申请日：1999-02-25
申请人： UNIV JOHNS HOPKINS MED
发明人： HE TONG-CHUAN , VOGELSTEIN BERT , KINZLER KENNETH W
IPC分类号： C12N15/86 , C07K14/075 , C12N5/10 , C12N7/00 , C12N15/00 , C12N15/861 , C12R1/01
摘要： Recombinant adenoviruses provide a versatile system for gene expression studies and therapeutic applications. This invention describes a strategy which simplifies the generation and production of such viruses. A recombinant adenoviral plasmid is generated with a minimum of enzymatic manipulations, employing homologous recombination in bacteria rather than in eucaryotic cells. Following transfections of such plasmids into a mammalian packaging cell line, viral production can be conveniently followed with the aid of green fluorescent protein, encoded by a gene incorporated into the viral backbone. Homogeneous viruses can be obtained from this procedure without plaque purification. This system expedites the process of generating and testing recombinant adenoviruses.

7. 发明专利

AT267868T 未知
公开(公告)号：AT267868T
公开(公告)日：2004-06-15
申请号：AT99943741
申请日：1999-08-20
申请人： UNIV JOHNS HOPKINS MED
发明人： HE TONG-CHUAN , VOGELSTEIN BERT , KINZLER KENNETH W
IPC分类号： C12N15/09 , A61K31/711 , A61K38/00 , A61K45/00 , A61K48/00 , A61P35/00 , C07K14/47 , C12N15/12 , C12Q1/02 , C12Q1/68 , C12Q1/6897 , G01N33/15 , G01N33/50 , C12N15/63 , C07K14/27
摘要： The APC tumor suppressor protein binds to beta -catenin, a protein recently shown to interact with Tcf/Lef transcription factors. Here, the gene encoding a Tcf family member that is expressed in colonic epithelium (hTcf-4) was cloned and characterized. hTcf-4 transactivates transcription only when associated with beta -catenin. Nuclei of APC-/- colon carcinoma cells were found to contain a stable beta -catenin-hTCF-4 complex that was constitutively active, as measured by transcription of a Tcf reporter gene. Reintroduction of APC removed beta -catenin from hTcf4 and abrogated the transcriptional transactivation. Constitutive transcription of TCF target genes, caused by loss of APC function, may be a crucial event in the early transformation of colonic epithelium. It is also shown here that the products of mutant APC genes found in colorectal tumors are defective in regulating beta -catenin/Tcf-4 transcriptional activation. Furthermore, colorectal tumors with intact APC genes were shown to contain subtle activating mutations of beta -catenin that altered functionally significant phosphorylation sites. These results indicate that regulation of beta -catenin is critical to APC's tumor suppressive effect and that this regulation can be circumvented by mutations in either APC or beta -catenin.

8. 发明专利

AU747847B2 A simplified system for generating recombinant adenoviruses 未知
公开(公告)号：AU747847B2
公开(公告)日：2002-05-23
申请号：AU2787599
申请日：1999-02-25
申请人： UNIV JOHNS HOPKINS MED
发明人： HE TONG-CHUAN , VOGELSTEIN BERT , KINZLER KENNETH W
IPC分类号： C07K14/075 , C12N15/861 , C12N15/86 , C12N5/10 , C12N15/00 , C12N7/00
摘要： Recombinant adenoviruses provide a versatile system for gene expression studies and therapeutic applications. This invention describes a strategy which simplifies the generation and production of such viruses. A recombinant adenoviral plasmid is generated with a minimum of enzymatic manipulations, employing homologous recombination in bacteria rather than in eucaryotic cells. Following transfections of such plasmids into a mammalian packaging cell line, viral production can be conveniently followed with the aid of green fluorescent protein, encoded by a gene incorporated into the viral backbone. Homogeneous viruses can be obtained from this procedure without plaque purification. This system expedites the process of generating and testing recombinant adenoviruses.

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