Chemistry: molecular biology and microbiology – Measuring or testing process involving enzymes or... – Involving nucleic acid
Reexamination Certificate
1998-01-07
2001-07-24
Budens, Robert D. (Department: 1648)
Chemistry: molecular biology and microbiology
Measuring or testing process involving enzymes or...
Involving nucleic acid
C435S007920, C436S504000, C530S350000, C530S351000, C530S358000, C530S395000, C530S412000
Reexamination Certificate
active
06265160
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates generally to the field of transmembrane signal transduction. More specifically, the invention relates to the biochemical activation of IL-2 inducible transcription factors.
BACKGROUND OF THE INVENTION
The interaction of interleukin-2 (IL-2) with its receptor regulates the magnitude and duration of the T cell response to antigen. IL-2 signalling requires dimerization of the cytoplasmic domains of the &bgr; chain (IL-2R&bgr;) and &ggr; chain (IL-2R&ggr;) of the IL-2 receptor. IL-2R&ggr; is referred to as the common cytokine receptor &ggr; chain (&ggr;
c
), because it is a component of the receptors for IL-2, IL4, IL-7, IL-9 and IL-15. Like other members of the cytokine receptor superfamily, neither the IL-2R&bgr; nor the &ggr;
C
chain has intrinsic catalytic activity. The IL-2R&bgr; chain is shared by the receptors for IL-2 and IL-15 (Giri et al.,
EMBO J.
13:2822 (1994)). IL-2 rapidly activates Stat5 in resting peripheral blood lymphocytes (PBL) and activates both Stat5 and Stat3 in PBL that have been protreated with phytohemagglutinin (PHA).
Tyrosine phosphorylation of cellular proteins, including IL-2R&bgr; (Asao at al.,
J Exp. Med.
171:637 (1990); Mills et al.,
J. Biol Chem.
265:3561 (1990)), is one of the earliest events which follows IL-2 stimulation of responsive target cells. Those having ordinary skill in the art will appreciate that tyrosine phosphorylation can create docking sites for downstream signalling molecules having SH2 domains Signaling molecules in this category include, for example, Shc, Src, Grb2, PI 3-kinase, GAP, PTP-1D, and PLC-&ggr; in the case of the epidermal growth factor receptor, and Zap70 and Syk tyrosine kinases in the case of the T-cell and B-cell antigen receptors.
In contrast to some other signalling systems, phosphotyrosine docking sites have not been shown to be essential for IL-2 induced cellular proliferation. IL-2 signalling requires the heterodimerization of the IL-2&bgr; and &ggr;
c
chain cytoplasmic domains (Nakamura et al.,
Nature
369:330 (1994); Nelson et al.,
Nature
369:333 (1994)). This heterodimerization promotes the interaction of receptor-associated molecules and activates signalling pathways.
SUMMARY OF THE INVENTION
Agents which inhibit the Jak-Stat signal transduction pathway are identified in order to identify candidate drugs for treatment of proliferative disorders. Identification methods are alternatively based on inhibiting the interaction of: (1) the activated Stat3 and Stat5 transcription factors with an electrophoretic mobility shift assay probe, or (2) the Stat3 or Stat5 proteins with the IL-2R&bgr; chain of the IL-2 receptor.
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Budens Robert D.
Knobbe Martens Olson & Bear LLP
The United States of America as represented by the Department of
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