Chemistry: molecular biology and microbiology – Micro-organism – tissue cell culture or enzyme using process... – Recombinant dna technique included in method of making a...
Reexamination Certificate
1998-09-21
2002-08-27
Caputa, Anthony G. (Department: 1642)
Chemistry: molecular biology and microbiology
Micro-organism, tissue cell culture or enzyme using process...
Recombinant dna technique included in method of making a...
C435S041000, C435S069500, C435S325000, C530S300000, C530S350000, C536S001001, C536S001110, C536S018700, C536S022100, C536S023100
Reexamination Certificate
active
06440694
ABSTRACT:
FIELD OF THE INVENTION
The invention relates to a novel tumor necrosis factor (TNF) homolog designated herein as TNF-related death ligand (TRDL).
BACKGROUND OF THE INVENTION
Tumor necrosis factor (TNF), named for its ability to shrink tumors, is made by cells of the immune system and is a member of an emerging family of cytokines with important roles in immune regulation, inflammation and cancer. The family includes seven members, in addition to TNF, which share limited sequence homology that is confined to the C-terminal portion of the molecules. With exception of TNF-&bgr;, each of these of ligands are type II membrane associated proteins that require cell surface presentation to elicit effects from corresponding target cells (Wiley, S. R., Schooley, K., Smolak, P. J., Din, W. S., Huang, C-P., Nicholl, J. K., Sutherland, G. R., Davis Smith, T., Rauch, C., Smith, C. A., and Goodwin, R. G. (1995) Identification and characterization of a new member of the TNF family that induces apoptosis.
Immunity.
3, 673-682). This cytokine family interacts with a growing list of target transmembrane receptors with complicated signaling strategies and often contradictory biological effects (Wiley, S. R., Schooley, K., Smolak, P. J., Din, W. S., Huang, C-P., Nicholl, J. K., Sutherland, G. R., Davis Smith, T., Rauch, C., Smith, C. A., and Goodwin, R. G. (1995) Identification and characterization of a new member of the TNF family that induces apoptosis.
Immunity.
3, 673-682).
The interaction of TNF-&agr; with the TNFR-1 receptor typifies the biological diversity of the TNF ligand receptor family. Ligation of TNFR-1 can activate NF-&kgr;B and elicit an inflammatory response in a variety of cell types (Beg, A. A. and Baltimore, D. (1996) An essential role for NF-&kgr;B in preventing TNF-&agr;-induced cell death.
Science.
274, 782-784. Wang, C-Y., Mayo, M. W., and Baldwin, A. S. Jr. (1996) TNF-and cancer therapy-induced apoptosis: potentiation by inhibition of NF-&kgr;B.
Science.
274, 784-787. VanAntwerp, D. J., Martin, S. J., Kafri, T., Green, D. R., and Verma, I. M. (1996) Suppression of TNF-&agr;-induced apoptosis by NF-&kgr;B.
Science.
274, 787-789).
Alternatively, TNFR-1 activation can also induce apoptosis (Pan, G., O'Rourke, K, Chinnaiyan, A. M., Gentz, R., Ebner, R., Ni, J., and Dixit, V. (1997) The receptor for the cytotoxic ligand TRAIL.
Science.
276, 111-113). The mechanisms that regulate these two pathways and the final cellular outcome remain unclear, but offer interesting prospects for therapeutic intervention. The importance of this life death balance in human disease can be seen in the observation that TNF fails to efficiently kill many types of cancer cells (Wang, C-Y., Mayo, M. W., and Baldwin, A. S. Jr. (1996) TNF-and cancer therapy-induced apoptosis: potentiation by inhibition of NF-&kgr;B.
Science.
274, 784-787. Baichwal, V. R., and Baeuerle, P. A. (1997) Apoptosis: Activate NF-&kgr;B or die?
Current Biology.
7, R94-R96). Recent evidence suggests that TNF undermines its own killing powers by activating NF-&kgr;B, a key molecule that can block the apoptosis pathway (Beg, A. A. and Baltimore, D. (1996) An essential role for NF-&kgr;B in preventing TNF-&agr;-induced cell death.
Science.
274, 782-784. Wang, C-Y., Mayo, M. W., and Baldwin, A. S. Jr. (1996) TNF-and cancer therapy-induced apoptosis: potentiation by inhibition of NF-&kgr;B.
Science.
274, 784-787. VanAntwerp, D. J., Martin, S. J., Kafri, T., Green, D. R., and Verma, I. M. (1996) Suppression of TNF-&agr;-induced apoptosis by NF-&kgr;B.
Science.
274, 787-789. Liu, Z-G., Hsu, H., Goeddel, D., and Karin, M. (1996) Dissection of the TNF receptor 1 effector functions: JNK activation is not linked to apoptosis while NF-&kgr;B activation prevents cell death.
Cell.
87, 565-576. Wu, M., Lee, H., Bellas, R. E., Schauer, S. L., Arsura, M., Katz, D., FitzGerald, M. J., Rothstein, T. L., Sherr, D. H., and Sonenshein, G. E. (1996) Inhibition of NF-&kgr;B/Rel induces apoptosis of murine B cells.
EMBO J.
15, 4682-4690). This blockade may render tumor cells resistant to immune surveillance and confound chemotherapeutic approaches that rely on tumor cell apoptosis. Disruption of this protective mechanism may, therefore, sensitize cells to TNF mediated killing (Beg, A. A. and Baltimore, D. (1996) An essential role for NF-&kgr;B in preventing TNF-&agr;-induced cell death.
Science.
274, 782-784. Wang, C-Y., Mayo, M. W., and Baldwin, A. S. Jr. (1996) TNF-and cancer therapy-induced apoptosis: potentiation by inhibition of NF-&kgr;B.
Science.
274, 784-787. VanAntwerp, D. J., Martin, S. J., Kafri, T., Green, D. R., and Verma, I. M. (1996) Suppression of TNF-&agr;-induced apoptosis by NF-&kgr;B.
Science.
274, 787-789).
Recent advances in the understanding of TNF signaling have elucidated discrete molecular targets for potential blockade of NF-&kgr;B activation and apoptosis in cells responding to TNF (Beg, A. A. and Baltimore, D. (1996) An essential role for NF-&kgr;B in preventing TNF-&agr;-induced cell death.
Science.
274, 782-784. Wang, C-Y., Mayo, M. W., and Baldwin, A. S. Jr. (1996) TNF-and cancer therapy-induced apoptosis: potentiation by inhibition of NF-&kgr;B.
Science.
274, 784-787. VanAntwerp, D. J., Martin, S. J., Kafri, T., Green, D. R., and Verma, I. M. (1996) Suppression of TNF-&agr;-induced apoptosis by NF-&kgr;B.
Science.
274, 787-789. Wu, M., Lee, H., Bellas, R. E., Schauer, S. L., Arsura, M., Katz, D., FitzGerald, M. J., Rothstein, T. L., Sherr, D. H., and Sonenshein, G. E. (1996) Inhibition of NF-&kgr;B/Rel induces apoptosis of murine B cells.
EMBO J.
15, 4682-4690). These responses are facilitated by the recruitment of signaling proteins to activated TNF receptors. Some of these signaling proteins, including TRADD (TNFR1-associated death domain protein), TRAF2 (TNFR-associated protein-2) and RIP (receptor interacting protein kinase) appear to initiate activation of NF-&kgr;B. Chinnaiyan, A. M., O'Rourke, K, Yu, G-L., Lyons, R. H., Garg, M., Duan, D. R., Xing, L., Gentz, R., Ni, J., and Dixit, V. M. (1996) Signal transduction by DR3, a death domain-containing receptor related to TNFR-1 and CD95.
Science.
274, 990-992. Recruitment of other proteins, including FADD (Fas-associated death domain protein) and FLICK (FADD-like interleukin converting enzyme) induces apoptosis (Boldin, M. P., Goncharov, T. M., Goltsev, Y. V., and Wallach, D. (1996) Involvement of MACH, a novel MORT1/FADD-interacting protease, in Fas/APO-1-and TNF receptor-induced cell death.
Cell.
85, 803-815. Muzio, M., Chinnaiyan, A. M., Kischkel, F. C., O'Rourke, K., Shevchenko, A., Ni, J., Scaffidi, C., Bretz, J. D., Zhang, M., Gentz, R., Mann, M., Krammer, P. H., Peter, M. E., and Dixit, V. (1996) FLICE, a novel FADD-homologous ICE/CED-3-like protease, is recruited to the CD95 (Fas/APO-1) death-inducing signaling complex.
Cell.
85, 817-827).
This emerging biology has created considerable interest among researchers for potential therapeutic intervention, particularly in cancer, inflammatory diseases, and neurodegenerative disorders. Thus, it will be clear to the skilled artisan that there is a continuing need for novel members of the TNF family of inflammatory cytokines involved in apoptosis and NF-&kgr;B activation.
INFORMATION DISCLOSURE
Wiley et al.,
Immunity
3, 673-682 (1995).
Beg, A. A. and D. Baltimore,
Science
274, 782-784 (1996).
Wang et al.,
Science
274, 784-787 (1996).
VanAntwerp et al.,
Science
274, 787-789 (1996).
Pan et al.,
Science
276, 111-113 (1997).
Baichwal et al.,
Current Biology
7, R94-R96 (1997).
Liu et al.,
Cell
87, 565-576 (1996).
Wu et al.,
EMBO J
15, 4682-4690 (1996).
Chinnaiyan et al.,
Science
274, 990-992 (1996).
Boldin et al.,
Cell
85, 803-815 (1996).
Muzio et al.,
Cell
85, 817-827 (1996).
Altschul et al.,
J. Mol. Bio.
215, 403-410 (1990).
Idziorek et al.,
J. Immuno. Meth.
185:249-258 (1995).
X. M. Wang, et al.,
Human Immunol
37: 264 (1993).
SUMMARY OF THE INVENTION
The present invention provides isolated nucleic acid molecules comprising a po
Bienkowski Michael J.
Jones David A.
Mills Cynthia J.
Caputa Anthony G.
Harris Alana M.
Kerber Lori L.
Pharmacia & Upjohn Company
Rehberg Edward F.
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