Chemistry: molecular biology and microbiology – Measuring or testing process involving enzymes or... – Involving antigen-antibody binding – specific binding protein...
Patent
1996-07-02
1998-03-24
Guzo, David
Chemistry: molecular biology and microbiology
Measuring or testing process involving enzymes or...
Involving antigen-antibody binding, specific binding protein...
530327, 530330, C07K 700, C07K 704, G01N 3353
Patent
active
057311552
DESCRIPTION:
BRIEF SUMMARY
BACKGROUND OF THE INVENTION
(1) Field of the Invention
This invention relates in general to the activity of cytokines that utilize the STAT family of transcription factors for inducing cellular responses including interferon.gamma. (IFN.gamma.), interleukin-10 (IL-10) and the like, and more particularly to a composition capable of the intracellular inhibition of a cytokine-activatable STAT-family transcription factor that is involved in the activation of genes inducible by the cytokine, and to methods for inhibiting such a transcription factor.
(2) Description of Background Art
Cytokines are a group of regulatory polypeptides involved in the inductive and effector phases of immunologic and inflammatory responses. High affinity cell surface receptors bind the cytokine molecules and this event is converted into an intracellular signal that is transmitted to the nucleus. This membrane-to-nucleus. transduction pathway almost universally involves tyrosine phosphorylation of one or more transcription factors. (Hunter, Nature 366:114-116 which is incorporated by reference).
One family of latent cytoplasmic proteins that serve as cytokine transcription factors has been termed STAT (signal transducers and activators of transcription). There are six known members of the STAT family, STAT 1 (p91), STAT 2 (p113), STAT3 (APRF), STAT 4, STAT 5 (MGF) and IL-4 STAT. (Hou et al., Science 265:1701-1706, 1994 which is incorporated by reference). The STAT family of transcription factors share some sequence similarities. These include a carboxy-terminal SH3 domain followed by an SH2 domain; homologous regions in the amino-terminal region; and a conserved tyrosine near the carboxy terminus that is phosphorylated and is essential for function. (Ihle et al., TIBS 19:222-227, 1994; Shuai et al. Science 261:1744-1746, 1994 which are incorporated by reference). The STAT transcription factors become activated through phosphorylation of tyrosine residues. The STAT proteins are then translocated to the nucleus in homodimeric or in heterocomplexed form. Here they bind to specific sequences or response elements and stimulate transcription. (for review see Darnell et al., Science 264:1415-1421. 1994 which is incorporated by reference). The cytokine-induced Intracellular signal transduction by STAT family members is exemplified by studies with Interferon.gamma. (IFN.gamma.) and Interleukin-10 (IL-10).
Interferon.gamma. is an important cytokine derived from T cells and natural killer cells that plays important roles in promoting host defense and immunopathologic processes. IFN.gamma. exerts its pleiotropic effects on cells through an interaction with a specific high affinity receptor expressed at the cell surface. Functionally active receptors require the presence of two distinct species specific polypeptides: a 90 kDa .alpha. chain that is both necessary and sufficient for IFN.gamma. binding and processing and necessary but not sufficient for biologic response induction, and a second recently cloned polypeptide now denoted as the IFN.gamma. receptor .beta. chain needed exclusively for development of functional responses in cells (Jung et al., 1987; Jung et al., 1990; Fischer et al., 1990; Farrar et al. 1991; Gibbs et al., 1991 all of which are incorporated by reference). Although the function of the receptor .beta. chain remains unclear, the structure-function relationships that exist within the receptor .alpha. chain have been the focus of a number of recent studies (Farrar et al., 1991; Farrar et al., 1992 which is incorporated by reference). Specifically, these analyses have revealed two topographically distinct, functionally important regions within the receptor .alpha. chain's intracellular domain. The first is comprised of 48 amino acids, proximal to the receptor's transmembrane domain (amino acids 256-303), and contains elements required for both receptor-mediated ligand internalization and biologic response induction (enhancement of MHC class I expression) (Farrar et al., 1991 which is incorporated by reference). The second region
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Farrar Michael A.
Greenlund Andrew C.
Schreiber Robert D.
Guzo David
Washington University
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