公开(公告)号：US06197925B1

公开(公告)日：2001-03-06

申请号：US08260174

申请日：1994-06-13

申请人： Gerald R. Crabtree ,  Jeffrey P. Northrop ,  Steffan N. Ho

发明人： Gerald R. Crabtree ,  Jeffrey P. Northrop ,  Steffan N. Ho

IPC分类号： C07K500

CPC分类号： A61K31/70 ,  A61K38/1709 ,  C07K14/4702 ,  C07K14/4705 ,  C12Q1/6876 ,  C12Q1/6897 ,  C12Q2600/158 ,  G01N33/6872 ,  G01N2500/02 ,  A61K2300/00

摘要： The invention provides novel polypeptides which are associated with the transcription complex NF-AT, polynucleotides encoding such polypeptides, antibodies which are reactive with such polypeptides, polynucleotide hybridization probes and PCR amplification probes for detecting polynucleotides which encode such polypeptides, transgenes which encode such polypeptides, homologous targeting constructs that encode such polypeptides and/or homologously integrate in or near endogenous genes encoding such polypeptides, nonhuman transgenic animals which comprise functionally disrupted endogenous genes that normally encode such polypeptides, and transgenic nonhuman animals which comprise transgenes encoding such polypeptides. The invention also provides methods for detecting T cells (including activated T cells) in a cellular sample, methods for treating hyperactive or hypoactive T cell conditions, methods for screening for immunomodulatory agents, methods for diagnostic staging of lymphocyte differentiation, methods for producing NF-AT proteins for use as research or diagnostic reagents, methods for producing antibodies reactive with the novel polypeptides, and methods for producing transgenic nonhuman animals.

公开(公告)号：US6150099A

公开(公告)日：2000-11-21

申请号：US37143

申请日：1998-03-09

申请人： Gerald R. Crabtree ,  Jeffrey P. Northrop ,  Steffan N. Ho

发明人： Gerald R. Crabtree ,  Jeffrey P. Northrop ,  Steffan N. Ho

IPC分类号： G01N33/53 ,  A61K38/00 ,  A61K38/17 ,  A61K48/00 ,  A61P37/00 ,  C07H21/02 ,  C07H21/04 ,  C07K14/47 ,  C07K14/52 ,  C12N5/10 ,  C12N15/09 ,  C12N15/12 ,  C12P21/02 ,  C12Q1/68 ,  C12R1/91 ,  G01N33/531 ,  G01N33/68

CPC分类号： A61K31/70 ,  A61K38/1709 ,  C07K14/4702 ,  C07K14/4705 ,  C12Q1/6876 ,  C12Q1/6897 ,  G01N33/6872 ,  C12Q2600/158 ,  G01N2500/02

摘要： The invention provides novel polypeptides which are associated with the transcription complex NF-AT, polynucleotides encoding such polypeptides, antibodies which are reactive with such polypeptides, polynucleotide hybridization probes and PCR amplification probes for detecting polynucleotides which encode such polypeptides, transgenes which encode such polypeptides, homologous targeting constructs that encode such polypeptides and/or homologously integrate in or near endogenous genes encoding such polypeptides, nonhuman transgenic animals which comprise functionally disrupted endogenous genes that normally encode such polypeptides, and transgenic nonhuman animals which comprise transgenes encoding such polypeptides. The invention also provides methods for detecting T cells (including activated T cells) in a cellular sample, methods for treating hyperactive or hypoactive T cell conditions, methods for screening for immunomodulatory agents, methods for diagnostic staging of lymphocyte differentiation, methods for producing NF-AT proteins for use as research or diagnostic reagents, methods for producing antibodies reactive with the novel polypeptides, and methods for producing transgenic nonhuman animals.

公开(公告)号：US06352830B1

公开(公告)日：2002-03-05

申请号：US09232346

申请日：1999-01-15

申请人： Gerald R. Crabtree ,  Jeffrey P. Northrop ,  Steffan N. Ho ,  William M. Flanagan

发明人： Gerald R. Crabtree ,  Jeffrey P. Northrop ,  Steffan N. Ho ,  William M. Flanagan

IPC分类号： C12Q168

CPC分类号： A61K31/70 ,  A61K38/1709 ,  C07K14/4702 ,  C07K14/4705 ,  C12Q1/6876 ,  C12Q1/6897 ,  C12Q2600/158 ,  G01N33/6872 ,  G01N2500/02 ,  A61K2300/00

摘要： The invention provides novel polypeptides which are associated with the transcription complex NF-AT, polynucleotides encoding such polypeptides, antibodies which are reactive with such polypeptides, polynucleotide hybridization probes and PCR amplification probes for detecting polynucleotides which encode such polypeptides, transgenes which encode such polypeptides, homologous targeting constructs that encode such polypeptides and/or homologously integrate in or near endogenous genes encoding such polypeptides, nonhuman transgenic animals which comprise functionally disrupted endogenous genes that normally encode such polypeptides, and transgenic nonhuman animals which comprise transgenes encoding such polypeptides. The invention also provides methods for detecting T cells (including activated T cells) in a cellular sample, methods for treating hyperactive or hypoactive T cell conditions, methods for screening for immunomodulatory agents, methods for diagnostic staging of lymphocyte differentiation, methods for producing NF-AT proteins for use as research or diagnostic reagents, methods for producing antibodies reactive with the novel polypeptides, and methods for producing transgenic nonhuman animals. Also included are methods and agents for activation of NF-AT dependent transcription, including agents which interfere with the production, modification of nuclear or cytoplasmic subunits, or the nuclear import of the cytoplasmic subunits. In particular, screening tests for novel immunosuppressants are provided based upon the ability of NF-AT to activate transcription.

摘要翻译： 本发明提供与转录复合体NF-AT相关的新型多肽，编码这些多肽的多核苷酸，与这些多肽反应的抗体，用于检测编码这种多肽的多核苷酸的多核苷酸杂交探针和PCR扩增探针，编码这些多肽的转基因， 编码此类多肽的同源靶向构建体和/或同源地整合编码此类多肽的内源基因或其附近，包含通常编码该多肽的功能性破坏性内源基因的非人类转基因动物以及包含编码此类多肽的转基因的转基因非人动物。 本发明还提供了用于检测细胞样品中T细胞（包括活化T细胞）的检测方法，用于治疗多动症或低反应性T细胞病症的方法，免疫调节剂筛选方法，淋巴细胞分化诊断分期方法， 用作研究或诊断试剂的AT蛋白，用于产生与新多肽反应的抗体的方法，以及用于产生转基因非人动物的方法。 还包括用于激活NF-AT依赖性转录的方法和试剂，包括干扰核或细胞质亚基的产生，修饰或者细胞质亚基的核进入的试剂。 特别地，基于NF-AT激活转录的能力提供新型免疫抑制剂的筛选试验。

公开(公告)号：US6096515A

公开(公告)日：2000-08-01

申请号：US37190

申请日：1998-03-09

申请人： Gerald R. Crabtree ,  Jeffrey P. Northrop ,  Steffan N. Ho

发明人： Gerald R. Crabtree ,  Jeffrey P. Northrop ,  Steffan N. Ho

IPC分类号： G01N33/53 ,  A61K38/00 ,  A61K38/17 ,  A61K48/00 ,  A61P37/00 ,  C07H21/02 ,  C07H21/04 ,  C07K14/47 ,  C07K14/52 ,  C12N5/10 ,  C12N15/09 ,  C12N15/12 ,  C12P21/02 ,  C12Q1/68 ,  C12R1/91 ,  G01N33/531 ,  G01N33/68 ,  C12N15/00 ,  C12N15/63 ,  C12N15/85 ,  C12P19/34

CPC分类号： A61K31/70 ,  A61K38/1709 ,  C07K14/4702 ,  C07K14/4705 ,  C12Q1/6876 ,  C12Q1/6897 ,  G01N33/6872 ,  C12Q2600/158 ,  G01N2500/02

摘要： The invention provides novel polypeptides which are associated with the transcription complex NF-AT, polynucleotides encoding such polypeptides, antibodies which are reactive with such polypeptides, polynucleotide hybridization probes and PCR amplification probes for detecting polynucleotides which encode such polypeptides, transgenes which encode such polypeptides, homologous targeting constructs that encode such polypeptides and/or homologously integrate in or near endogenous genes encoding such polypeptides, nonhuman transgenic animals which comprise functionally disrupted endogenous genes that normally encode such polypeptides, and transgenic nonhuman animals which comprise transgenes encoding such polypeptides. The invention also provides methods for detecting T cells (including activated T cells) in a cellular sample, methods for treating hyperactive or hypoactive T cell conditions, methods for screening for immunomodulatory agents, methods for diagnostic staging of lymphocyte differentiation, methods for producing NF-AT proteins for use as research or diagnostic reagents, methods for producing antibodies reactive with the novel polypeptides, and methods for producing transgenic nonhuman animals.

摘要翻译： 本发明提供与转录复合体NF-AT相关的新型多肽，编码这些多肽的多核苷酸，与这些多肽反应的抗体，用于检测编码这种多肽的多核苷酸的多核苷酸杂交探针和PCR扩增探针，编码这些多肽的转基因， 编码此类多肽的同源靶向构建体和/或同源地整合编码此类多肽的内源基因或其附近，包含通常编码该多肽的功能性破坏性内源基因的非人类转基因动物以及包含编码此类多肽的转基因的转基因非人动物。 本发明还提供了用于检测细胞样品中T细胞（包括活化T细胞）的检测方法，用于治疗多动症或低反应性T细胞病症的方法，免疫调节剂筛选方法，淋巴细胞分化诊断分期方法， 用作研究或诊断试剂的AT蛋白，用于产生与新多肽反应的抗体的方法，以及用于产生转基因非人动物的方法。

公开(公告)号：US06875571B2

公开(公告)日：2005-04-05

申请号：US10040430

申请日：2002-01-07

申请人： Gerald R. Crabtree ,  Jeffrey P. Northrop ,  Steffan N. Ho ,  William M. Flanagan

发明人： Gerald R. Crabtree ,  Jeffrey P. Northrop ,  Steffan N. Ho ,  William M. Flanagan

IPC分类号： A61K38/00 ,  A61K38/17 ,  C07K14/47 ,  C12Q1/68 ,  G01N33/68 ,  C07H21/04 ,  C07K14/435 ,  G01N33/53

CPC分类号： A61K31/70 ,  A61K38/1709 ,  C07K14/4702 ,  C07K14/4705 ,  C12Q1/6876 ,  C12Q1/6897 ,  C12Q2600/158 ,  G01N33/6872 ,  G01N2500/02 ,  A61K2300/00

摘要： The invention provides novel polypeptides which are associated with the transcription complex NF-AT, polynucleotides encoding such polypeptides, antibodies which are reactive with such polypeptides, polynucleotide hybridization probes and PCR amplification probes for detecting polynucleotides which encode such polypeptides, transgenes which encode such polypeptides, homologous targeting constructs that encode such polypeptides and/or homologously integrate in or near endogenous genes encoding such polypeptides, nonhuman transgenic animals which comprise functionally disrupted endogenous genes that normally encode such polypeptides, and transgenic nonhuman animals which comprise transgenes encoding such polypeptides. The invention also provides methods for detecting T cells (including activated T cells) in a cellular sample, methods for treating hyperactive or hypoactive T cell conditions, methods for screening for immunomodulatory agents, methods for diagnostic staging of lymphocyte differentiation, methods for producing NF-AT proteins for use as research or diagnostic reagents, methods for producing antibodies reactive with the novel polypeptides, and methods for producing transgenic nonhuman animals. Also included are methods and agents for activation of NF-AT dependent transcription, including agents which interfere with the production, modification of nuclear or cytoplasmic subunits, or the nuclear import of the cytoplasmic subunits. In particular, screening tests for novel immunosuppressants are provided based upon the ability of NF-AT to activate transcription.

摘要翻译： 本发明提供与转录复合体NF-AT相关的新型多肽，编码这些多肽的多核苷酸，与这些多肽反应的抗体，用于检测编码这种多肽的多核苷酸的多核苷酸杂交探针和PCR扩增探针，编码这些多肽的转基因， 编码此类多肽的同源靶向构建体和/或同源地整合编码此类多肽的内源基因或其附近，包含通常编码该多肽的功能性破坏性内源基因的非人类转基因动物以及包含编码此类多肽的转基因的转基因非人动物。 本发明还提供了用于检测细胞样品中T细胞（包括活化T细胞）的检测方法，用于治疗多动症或低反应性T细胞病症的方法，免疫调节剂筛选方法，淋巴细胞分化诊断分期方法， 用作研究或诊断试剂的AT蛋白，用于产生与新多肽反应的抗体的方法，以及用于产生转基因非人动物的方法。 还包括用于激活NF-AT依赖性转录的方法和试剂，包括干扰核或细胞质亚基的产生，修饰或者细胞质亚基的核进入的试剂。 特别地，基于NF-AT激活转录的能力提供新型免疫抑制剂的筛选试验。

公开(公告)号：US06388052B1

公开(公告)日：2002-05-14

申请号：US09037192

申请日：1998-03-09

申请人： Gerald R. Crabtree ,  Jeffrey P. Northrop ,  Steffan N. Ho

发明人： Gerald R. Crabtree ,  Jeffrey P. Northrop ,  Steffan N. Ho

IPC分类号： C07K500

CPC分类号： A61K31/70 ,  A61K38/1709 ,  C07K14/4702 ,  C07K14/4705 ,  C12Q1/6876 ,  C12Q1/6897 ,  C12Q2600/158 ,  G01N33/6872 ,  G01N2500/02 ,  A61K2300/00

摘要： The invention provides novel polypeptides which are associated with the transcription complex NF-AT, polynucleotides encoding such polypeptides, antibodies which are reactive with such polypeptides, polynucleotide hybridization probes and PCR amplification probes for detecting polynucleotides which encode such polypeptides, transgenes which encode such polypeptides, homologous targeting constructs that encode such polypeptides and/or homologously integrate in or near endogenous genes encoding such polypeptides, nonhuman transgenic animals which comprise functionally disrupted endogenous genes that normally encode such polypeptides, and transgenic nonhuman animals which comprise transgenes encoding such polypeptides. The invention also provides methods for detecting T cells (including activated T cells) in a cellular sample, methods for treating hyperactive or hypoactive T cell conditions, methods for screening for immunomodulatory agents, methods for diagnostic staging of lymphocyte differentiation, methods for producing NF-AT proteins for use as research or diagnostic reagents, methods for producing antibodies reactive with the novel polypeptides, and methods for producing transgenic nonhuman animals.

摘要翻译： 本发明提供与转录复合体NF-AT相关的新型多肽，编码这些多肽的多核苷酸，与这些多肽反应的抗体，用于检测编码这种多肽的多核苷酸的多核苷酸杂交探针和PCR扩增探针，编码这些多肽的转基因， 编码此类多肽的同源靶向构建体和/或同源地整合编码此类多肽的内源基因或其附近，包含通常编码该多肽的功能性破坏性内源基因的非人类转基因动物以及包含编码此类多肽的转基因的转基因非人动物。 本发明还提供了用于检测细胞样品中T细胞（包括活化T细胞）的检测方法，用于治疗多动症或低反应性T细胞病症的方法，免疫调节剂筛选方法，淋巴细胞分化诊断分期方法， 用作研究或诊断试剂的AT蛋白，用于产生与新多肽反应的抗体的方法，以及用于产生转基因非人动物的方法。

公开(公告)号：US06312899B1

公开(公告)日：2001-11-06

申请号：US09338128

申请日：1999-06-22

申请人： Gerald R. Crabtree ,  Jeffrey P. Northrop ,  Steffan N. Ho

发明人： Gerald R. Crabtree ,  Jeffrey P. Northrop ,  Steffan N. Ho

IPC分类号： C12Q168

CPC分类号： A61K31/70 ,  A61K38/1709 ,  C07K14/4702 ,  C07K14/4705 ,  C12Q1/6876 ,  C12Q1/6897 ,  C12Q2600/158 ,  G01N33/6872 ,  G01N2500/02 ,  A61K2300/00

摘要： The invention provides novel polypeptides which are associated with the transcription complex NF-AT, polynucleotides encoding such polypeptides, antibodies which are reactive with such polypeptides, polynucleotide hybridization probes and PCR amplification probes for detecting polynucleotides which encode such polypeptides, transgenes which encode such polypeptides, homologous targeting constructs that encode such polypeptides and/or homologously integrate in or near endogenous genes encoding such polypeptides, nonhuman transgenic animals which comprise functionally disrupted endogenous genes that normally encode such polypeptides, and transgenic nonhuman animals which comprise transgenes encoding such polypeptides. The invention also provides methods for detecting T cells (including activated T cells) in a cellular sample, methods for treating hyperactive or hypoactive T cell conditions, methods for screening for immunomodulatory agents, methods for diagnostic staging of lymphocyte differentiation, methods for producing NF-AT proteins for use as research or diagnostic reagents, methods for producing antibodies reactive with the novel polypeptides, and methods for producing transgenic nonhuman animals.

摘要翻译： 本发明提供与转录复合体NF-AT相关的新型多肽，编码这些多肽的多核苷酸，与这些多肽反应的抗体，用于检测编码这种多肽的多核苷酸的多核苷酸杂交探针和PCR扩增探针，编码这些多肽的转基因， 编码此类多肽的同源靶向构建体和/或同源地整合编码此类多肽的内源基因或其附近，包含通常编码该多肽的功能性破坏性内源基因的非人类转基因动物以及包含编码此类多肽的转基因的转基因非人动物。 本发明还提供了用于检测细胞样品中T细胞（包括活化T细胞）的检测方法，用于治疗多动症或低反应性T细胞病症的方法，免疫调节剂筛选方法，淋巴细胞分化诊断分期方法， 用作研究或诊断试剂的AT蛋白质，用于产生与新多肽反应的抗体的方法，以及用于产生转基因非人动物的方法。

公开(公告)号：US06171781B2

公开(公告)日：2001-01-09

申请号：US09049691

申请日：1998-03-27

申请人： Gerald R. Crabtree ,  Jeffrey P. Northrop ,  Steffan N. Ho

发明人： Gerald R. Crabtree ,  Jeffrey P. Northrop ,  Steffan N. Ho

IPC分类号： C12Q100

CPC分类号： A61K31/70 ,  A61K38/1709 ,  C07K14/4702 ,  C07K14/4705 ,  C12Q1/6876 ,  C12Q1/6897 ,  C12Q2600/158 ,  G01N33/6872 ,  G01N2500/02 ,  A61K2300/00

摘要： The invention provides novel polypeptides which are associated with the transcription complex NF-AT, polynucleotides encoding such polypeptides, antibodies which are reactive with such polypeptides, polynucleotide hybridization probes and PCR amplification probes for detecting polynucleotides which encode such polypeptides, transgenes which encode such polypeptides, homologous targeting constructs that encode such polypeptides and/or homologously integrate in or near endogenous genes encoding such polypeptides, nonhuman transgenic animals which comprise functionally disrupted endogenous genes that normally encode such polypeptides, and transgenic nonhuman animals which comprise transgenes encoding such polypeptides. The invention also provides methods for detecting T cells (including activated T cells) in a cellular sample, methods for treating hyperactive or hypoactive T cell conditions, methods for screening for immunomodulatory agents, methods for diagnostic staging of lymphocyte differentiation, methods for producing NF-AT proteins for use as research or diagnostic reagents, methods for producing antibodies reactive with the novel polypeptides, and methods for producing transgenic nonhuman animals.

公开(公告)号：US6063625A

公开(公告)日：2000-05-16

申请号：US156855

申请日：1998-09-16

申请人： Gerald R. Crabtree ,  Stuart L. Schreiber ,  David M. Spencer ,  Thomas J. Wandless ,  Steffan N. Ho ,  Peter Belshaw

发明人： Gerald R. Crabtree ,  Stuart L. Schreiber ,  David M. Spencer ,  Thomas J. Wandless ,  Steffan N. Ho ,  Peter Belshaw

IPC分类号： A61K38/00 ,  A61K47/48 ,  C07D498/18 ,  C07F5/02 ,  C07H19/01 ,  C07K7/64 ,  C07K14/395 ,  C07K14/705 ,  C07K14/71 ,  C07K14/725 ,  C12N15/62 ,  C12N15/63 ,  C12P15/00 ,  C12N15/00 ,  C12N15/85 ,  C12N15/86

CPC分类号： C07D498/18 ,  A61K47/48276 ,  C07F5/025 ,  C07H19/01 ,  C07K14/395 ,  C07K14/705 ,  C07K14/7051 ,  C07K14/71 ,  C07K7/645 ,  C12N15/62 ,  C12N15/63 ,  C12P15/00 ,  A61K38/00 ,  C07K2319/00 ,  C07K2319/02 ,  C07K2319/03 ,  C07K2319/035 ,  C07K2319/09 ,  C07K2319/20 ,  C07K2319/32 ,  C07K2319/42 ,  C07K2319/43 ,  C07K2319/60 ,  C07K2319/71 ,  C07K2319/715 ,  C07K2319/81 ,  C07K2319/90

摘要： Dimerization and oligomerization of proteins are general biological control mechanisms that contribute to the activation of cell membrane receptors, transcription factors, vesicle fusion proteins, and other classes of intra- and extracellular proteins. We have developed a general procedure for the regulated (inducible) dimerization or oligomerization of intracellular proteins. In principle, any two target proteins can be induced to associate by treating the cells or organisms that harbor them with cell permeable, synthetic ligands. To illustrate the practice of this invention, we have induced: (1) the intracellular aggregation of the cytoplasmic tail of the .zeta. chain of the T cell receptor (TCR)-CD3 complex thereby leading to signaling and transcription of a reporter gene, (2) the homodimerization of the cytoplasmic tail of the Fas receptor thereby leading to cell-specific apoptosis (programmed cell death) and (3) the heterodimerization of a DNA-binding domain (Gal4) and a transcription-activation domain (VP16) thereby leading to direct transcription of a reporter gene. Regulated intracellular protein association with our cell permeable, synthetic ligands offers new capabilities in biological research and medicine, in particular, in gene therapy. Using gene transfer techniques to introduce our artificial receptors, one can turn on or off the signaling pathways that lead to the overexpression of therapeutic proteins by administering orally active "dimerizers" or "de-dimerizers", respectively. Since cells from different recipients can be configured to have the pathway overexpress different therapeutic proteins for use in a variety of disorders, the dimerizers have the potential to serve as "universal drugs". They can also be viewed as cell permeable, organic replacements for therapeutic antisense agents or for proteins that would otherwise require intravenous injection or intracellular expression (e.g., the LDL receptor or the CFTR protein).

公开(公告)号：US6046047A

公开(公告)日：2000-04-04

申请号：US157230

申请日：1998-09-16

申请人： Gerald R. Crabtree ,  Stuart L. Schreiber ,  David M. Spencer ,  Thomas J. Wandless ,  Peter Belshaw ,  Steffan N. Ho

发明人： Gerald R. Crabtree ,  Stuart L. Schreiber ,  David M. Spencer ,  Thomas J. Wandless ,  Peter Belshaw ,  Steffan N. Ho

IPC分类号： A61K38/00 ,  A61K47/48 ,  A61K48/00 ,  C07D498/18 ,  C07F5/02 ,  C07H19/01 ,  C07K7/64 ,  C07K14/395 ,  C07K14/705 ,  C07K14/71 ,  C07K14/715 ,  C07K14/725 ,  C12N15/12 ,  C12N15/62 ,  C12N15/63 ,  C12P15/00 ,  C12P17/18 ,  C12N15/13 ,  C12N15/85

CPC分类号： C07D498/18 ,  A61K47/48276 ,  A61K48/00 ,  C07F5/025 ,  C07H19/01 ,  C07K14/395 ,  C07K14/705 ,  C07K14/7051 ,  C07K14/71 ,  C07K14/715 ,  C07K7/645 ,  C12N15/62 ,  C12N15/63 ,  C12P15/00 ,  C12P17/188 ,  A01K2217/05 ,  A61K38/00 ,  C07K2319/00 ,  C07K2319/02 ,  C07K2319/03 ,  C07K2319/035 ,  C07K2319/09 ,  C07K2319/20 ,  C07K2319/32 ,  C07K2319/42 ,  C07K2319/43 ,  C07K2319/60 ,  C07K2319/71 ,  C07K2319/715 ,  C07K2319/81 ,  C07K2319/90

摘要： Dimerization and oligomerization of proteins are general biological control mechanisms that contribute to the activation of cell membrane receptors, transcription factors, vesicle fusion proteins, and other classes of intra- and extracellular proteins. We have developed a general procedure for the regulated (inducible) dimerization or oligomerization of intracellular proteins. In principle, any two target proteins can be induced to associate by treating the cells or organisms that harbor them with cell permeable, synthetic ligands. To illustrate the practice of tis invention, we have induced: (1) the intracellular aggregation of the cytoplasmic tail of the .zeta. chain of the T cell receptor (TCR)-CD3 complex thereby leading to signaling and transcription of a reporter gene, (2) the homodimerization of the cytoplasmic tail of the Fas receptor thereby leading to cell-specific apoptosis (programmed cell death) and (3) the heterodimerization of a DNA-binding domain (Gal4) and a transcription-activation domain (VP16) thereby leading to direct transcription of a reporter gene. Regulated intracellular protein association with our cell permeable, synthetic ligands offers new capabilities in biological research and medicine, in particular, in gene therapy. Using gene transfer techniques to introduce our artificial receptors, one can turn on or off the signaling pathways that lead to the overexpression of therapeutic proteins by administering orally active "dimerizers" or "de-dimerizers", respectively. Since cells from different recipients can be configured to have the pathway overexpress different therapeutic proteins for use in a variety of disorders, the dimerizers have the potential to serve as "universal drugs". They can also be viewed as cell permeable, organic replacements for therapeutic antisense agents or for proteins that would otherwise require intravenous injection or intracellular expression (e.g., the LDL receptor or the CFTR protein).