Uses of THANK, a TNF homologue that activates apoptosis

Details Uses of THANK, a TNF homologue that activates apoptosis Uses of THANK, a TNF homologue that activates apoptosis

2000-02-01

2002-11-05

Caputa, Anthony C. (Department: 1642)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Peptide containing doai

C514S001000, C514S002600, C424S009100, C436S064000, C436S086000

Reexamination Certificate

active

06475986

ABSTRACT:

BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates generally to the fields of biochemistry and molecular oncology. More specifically, the present invention relates to uses of a novel cytokine, THANK, a TNF homologue that activates apoptosis, nuclear Factor-&kgr;B, and c-jun N-terminal kinase.
2. Description of the Related Art
In 1984, two homologous cytokines were reported to inhibit the growth of tumor cells specifically (1-7) and was named TNF-&agr; and TNF-&bgr; (also called lymphotoxin). Since then over 15 members of this family have been identified, including FasL, CD29L, CD30L, CD40L, OX-40L, 4-1BBL, LT-&bgr;, TWEAK, TRAIL, RANKL/TRANCE, LIGHT, VEGI, and APRIL (8-16). At the amino acid sequence level, various members of the TNF family are 20-25% homologous to each other. Most members of this family play an important role in gene activation, proliferation, differentiation, and apoptosis. These ligands interact with the corresponding receptor, also members of the TNF receptor family, and activate the transcription factors NF-&kgr;B and AP1 (9, 17), a stress-activated protein kinase (c-jun N-terminal protein kinase, JNK), and a cascade of caspases.
The prior art is deficient in the lack of uses of a novel member of the TNF family, named THANK, for TNF homologue that activates apoptosis, NF-&kgr;B, and JNK. For example, the prior art is deficient in the lack of applications of THANK in inhibiting tumor growth and applications of THANK inhibitors in inhibiting the activation of NF-&kgr;B. The present invention fulfills this long-standing need and desire in the art.
SUMMARY OF THE INVENTION
By searching an expressed sequence tag (EST) data base using the amino acid sequence motif of TNF, a novel member of the TNF family, named THANK, was identified for TNF homologue that activates apoptosis, NF-&kgr;B, and JNK. THANK was primarily expressed by hematopoietic cells. The recombinant THANK activated NF-&kgr;B, c-jun N-terminal kinase, caspase-3 and displayed anti-proliferative effects in U937 cells through binding sites distinct from those for TNF.
The present invention is directed to the applications of THANK, including using THANK inhibitors to inhibit the activation of NF-&kgr;B and to treat a pathological condition caused by the activation of NF-&kgr;B. Also provided is a method of inhibiting growth of a wide variety of tumor cells by administering THANK protein.
In one embodiment of the present invention, there is provided a method of inhibiting the activation of NF-&kgr;B in cells by treating the cells with a THANK inhibitor.
In another embodiment of the present invention, there is provided a method of treating a pathological condition caused by the activation of NF-&kgr;B in an individual by administering a THANK inhibitor in a therapeutically effective amount. Preferably, the pathological condition is selected from the group consisting of toxic shock, septic shock, acute phase response, viral infection, radiation susceptibility, atherosclerosis, cancer, acute inflammatory conditions, arthritis, allergy, and graft vs. host reaction.
In still another embodiment of the present invention, there is provided a method of inhibiting growth of tumor cells by administering a therapeutically effective amount of THANK protein. Preferably, the cells are selected from the group consisting of myeloid cells, colon cancer cells, prostate cancer cells, breast carcinoma cells, cervical carcinoma cells, chronic myeloid leukemic cells and acute myeloid leukemic cells. Still preferably, THANK protein is administered in a dose of from about 0.01 mg/kg of patient weight per day to about 100 mg/kg of patient weight per day.
Other and further aspects, features, and advantages o f the present invention will be apparent from the following description of the presently preferred embodiments of the invention given for the purpose of disclosure.


REFERENCES:
Amino acid database, Accession No. W73043, 1999.*
Amino acid database, Accession No. W62461, 1998.

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