Chemistry: molecular biology and microbiology – Animal cell – per se ; composition thereof; process of... – Primate cell – per se
Patent
1998-05-29
2000-12-26
Elliott, George C.
Chemistry: molecular biology and microbiology
Animal cell, per se ; composition thereof; process of...
Primate cell, per se
435325, 435350, 435351, 435354, 435355, 435366, 424 9321, C12N 510, C12N 506, C12N 508, A61K 4800
Patent
active
061657875
ABSTRACT:
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).
REFERENCES:
patent: 5171671 (1992-12-01), Evans et al.
Harding et al. (1989) "A Receptor for the Immunosuppressant FK506 is a cis-trans Peptidyl-Prolyl Isomerase" Nature 341, 758.
Schreiber et al. (1991) "Immunophilin-Ligand Complexes as Probes of Intracellular Signaling Pathways" Transplantation Proceedings, 23, 2839.
Schreiber et al. (1992) "Molecular Recognition of Immunophilins and Immunophilin-Ligand Complexes" Tetrahedron 148: 2545-2558.
Schreiber et al. (1991) "Protein Overproduction for Organic Chemists" Tetrahedron, 47, 2543-2562.
Rosen et al. (1992)"Natural Products as Probes of Cellular Function: Studies of Immunophilins" Angew. Chemie, Int. Ed. Eng., 31, 384-400.
Bram et al. (1993) "Identification of the Immunophilins Capable of Mediating Inhibition of Signal Transduction by Cyclosporin A and FK506: Roles of Calcineurin Binding and Cellular Location" Mol. Cell Biol., 13, 4760-4769.
Selvakumaran et al. (1993) "Myeloblastic leukemia cells conditionally blocked by Myc-estrogen receptor chimeric transgenes for terminal differentiation coupled to growth arrest and apoptosis" Blood, 81:2257.
Wandless T.J. (1993) "Turning genes on and off using FKBP and FK506" Doctoral Thesis.
Standaert R.F. (1992) "Biochemical and structural studies of the FK506- and rapamycin-binding proteins (FKBPs)" , Abstract of Doctoral Thesis.
Bierer et al. (1990) "Mechanisms of Immunosuppression by FK506: Preservation of T Cell Transmembrane Signal Transduction" Transplantation, 49, 1168.
Rosen et al. (1990) "Inhibition of FKBP Rotamase Activity by Immunosuppressant FK506: A Twisted Amide Surrogate" Science, 248, 863.
Bierer et al. (1990) "Two Distinct Signal Transmission Pathways in T Lymphocytes are Inhibited by Complexes Formed Between an Immunophilin and Either FK506 or Rapamycin" PNAS U. S. A., 87, 9231.
Albers et al. (1990) "Substrate Specificity for the Human Rotamase FKBP: A View of FK506 and Rapamycin as Leucine (twisted amide)-Proline Mimics" J. Org. Chem., 55, 4984.
Bierer et al. (1990) "Probing Immunosuppressant Action with a Nonnatural Immunophilin Ligand" Science, 250, 556.
Schreiber S.L. (1991) "Chemistry and Biology of the Immunophilins and Their Immunosuppressive Ligands" Science, 251, 283.
Fretz et al. (1991) "Rapamycin and FK506 Binding Proteins (Immunophilins)" J. Am. Chem. Soc., 113, 1409.
Bierer et al. (1991) "The Effect of the Immunosuppressant FK506 on Alternate Pathways of T Cell Activation" Eur. J. Immunol., 21, 439-445.
Wandless et al.(1991) "FK506 and Rapamycin Binding to FKBP: Common Elements Involved in Immunophilin-Ligand Complexation" J. Am. Chem. Soc., 113, 2339-2341.
Lane et al. (1991) "Complete Amino Acid Sequence of the FK506 and Rapamycin Binding Protein, FKBP, Isolated from Calf Thymus" J. Prot. Chem., 10, 151-160.
Hultsch et al. (1991) "Inhibition of IgE Receptor-Mediated Exocytosis from Rat Basophilic Leukemia Cells by FK506 is Reversed by Rapamycin: Evidence for Common Signaling Pathways in Mast Cells and T Lymphocytes" FASEB J., 5, A1008 (3705).
Rosen et al. (1991) "Proton and Nitrogen Sequential Assignments and Secondary Structure Determination of the Human FK506 and Rapamycin Binding Protein" Biochemistry, 30, 4774-4789.
Michnick et al. (1991) "Solution Structure of FKBP, a Rotamase Enzyme and Receptor for FK506 and Rapamycin" Science, 252, 836-839.
Van Duyne et al.(1991) "Atomic Structure of FKBP-FK506, an Immunophilin-Immunosuppressant Complex" Science, 252, 839-842.
Albers et al. (1991) "FKBP, Thought to Be Identical to PKCI-2, Does Not Inhibit Protein Kinase C" BioMed. Chem. Lett., 1, 205-210.
Albers et al. (1991)"The Relationship of FKBP to PKCI-2" Nature, 351, 527.
Hultsch et al. (1991) "Immunophilin Ligands Demonstrate Common Features of Signal Transduction Leading to Exocytosis or Transcription" PNAS USA, 88, 6229-6233.
Van Duyne et al. (1991) "Atomic Structure of the Rapamycin human immunophilin FKBP-12 complex" J. Am. Chem. Soc., 113, 7433.
Ullman et al. (1991) "Site of action of cyclosporine and FK506 in the pathways of communication between the T-lymhocyte antigen receptor and the early activation genes" Transplant. Proceed., 23, 2845.
Galat et al. (1992) "A Rapamycin-Selective 25 kDa Immunophilin" Biochemistry, 31, 2427-2434.
Schreiber et al.(1992) "The Mechanism of Action of Cyclosporin A and FK506" Immunology Today, 13, 136-142.
Liu et al. (1992) "Inhibition of T Cell Signaling by Immunophilin-Ligand Complexes Correlates With Loss of Calcineurin Phosphatase Activity" Biochemistry, 31, 3896-3901.
Francavilla et al. (1992) "Inhibition of Liver, Kidney, and Intestine Regeneration by Rapamycin" Transplantation, 53, 496-498.
Tai et al. (1992) "Association of a 59-Kilodalton Immunophilin with the Glucocorticoid Receptor Complex" Science, 256, 1315-1318.
Schreiber S.L.(1992) "Immunophilin-Sensitive Phophatase Action in Cell Signaling Pathways" Cell, 70, 365-368.
Kaye et al. (1992) "Effects of Cyclosporin A and FK506 on Fce Receptor type I-Initiated Increases in Cytokine mRNA in Mouse Bone Marrow-Derived Progenito Mast Cells: Resistance to FK506 is Associated with a Deficiency in FKBP12" PNAS USA, 89, 8542-8546.
DiLella et al.(1992) "Chromosomal Band Assignments of the Genes Encoding Human FKBP12 and FKBP13" Biochem. Biophys. Res. Commun., 189, 819-823.
Chung et al. (1992) "Rapamycin-FKBP specifically blocks growth-dependent activation of and signalling by the 70 kd S6 protein kinases" Cell, 69, 1227.
Flanagan et al. (1992) "Intracellular signal transmission: a novel role for the prolyl isomerases" J. Cell. Biochem. Suppl. 0 (16 Part A), 61, Abstract # B005.
Kao et al. (1992) "Nuclear target of cyclosporin A and FK506 action is specifically bound by a heterodimeric protein comprising molecular weights 90K and 45K" J. Cell. Biochem. Suppl. 0 (16 Part B), 239, Abstract #H 523.
Flanagan et al. (1992) "Nuclear association of a transcription factor essential for T cell activation by cyclosporin A and FK506" J. Cell. Biochem. Suppl. 0 (16 Part B), 237, Abstract # H514.
Serafini et al. (1992) "Selection and characterization of mutants in a signal transduction/transmission pathway" J. Cell. Biochem. Suppl. 0 (6 Part
Belshaw Peter
Crabtree Gerald R.
Schreiber Stuart L.
Spencer David M.
Wandless Thomas J.
Berstein David L.
Board of Trustees of Leland Stanford Jr. University
Clauss Isabelle M.
Elliott George C.
Hausdorff Sharon F.
LandOfFree
Regulated transcription of targeted genes and other biological e does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Regulated transcription of targeted genes and other biological e, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Regulated transcription of targeted genes and other biological e will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-993600