Organic compounds -- part of the class 532-570 series – Organic compounds – Carbohydrates or derivatives
Reexamination Certificate
1997-07-11
2001-01-09
Huff, Sheela (Department: 1642)
Organic compounds -- part of the class 532-570 series
Organic compounds
Carbohydrates or derivatives
C536S023100, C536S063000, C536S024100, C536S024310, C435S320100, C435S325000, C435S419000, C435S252300, C435S069100, C435S091100
Reexamination Certificate
active
06172211
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention is in the fields of molecular biology, cancer biology and medical therapeutics. The invention is generally directed to the identification of genes that inhibit the growth of, and induce apoptosis in, cancer cells, and to polypeptides encoded by such genes. In particular, the invention concerns the nucleotide sequence of one such tumor-inhibiting gene, tag7, the amino acid sequence of a polypeptide encoded by tag7, antibodies that specifically bind to the tag7 gene product, and methods of inhibiting cancer cell growth and of cancer therapy using the tag7 gene and gene product.
2. Related Art
Tumor Metastasis
The metastasis of tumor cells is a complex process which includes a complex cascade of events. Included among these events are the proliferation of tumor cells and blocking of the apoptosis mechanism (Harrington, E. A., et al.,
EMBO J
. 13:3286-3295 (1994)), the spread of the tumor cells into surrounding tissues, the penetration of tumor cells into the blood and lymphatic circulations, and the attachment and multiplication of tumor cells at a new site (Schirmacher, A. E.,
Adv. Cancer Res
. 43:1-42 (1985); Liotta, L. A., et al.,
Lab. Invest
. 49:636-649 (1983)). While the molecular mechanisms of the induction of the metastatic phenotype remain poorly studied, it is likely that activation and/or inactivation of a variety of regulatory and structural genes occur as a tumor becomes metastatic. Several genes whose expression correlates with the metastatic potential of tumors have been described (Yasushi, T., et al.,
J. Biol. Chem
. 269(37):22958-22963 (1994); Ebralidze, A. K., et al.,
Genetika
(
USSR
) 25(5):932-936 (1989); Wolf, C., et al.,
Proc. Natl. Acad. Sci. USA
90:1843-1847 (1993); Bernhard, E. J., et al.,
Proc. Natl. Acad. Sci. USA
91:4293-4297 (1994); Sato, H., et al.,
Nature
370:61-65 (1994)).
It has been suggested that the population of cells within a given tumor may be heterogeneous with respect to their metastatic potential (Fidler, I. J., and Hart, I. R.,
Science
217:998-1001 (1982)). This suggestion offers the possibility of obtaining related tumors that differ markedly in metastatic potential from one parent tumor. For example, tumors that are transplantable to mice and that have a varying frequency and organ-specificity of metastasis have been obtained (Senin, V. M.,
Vestin. Akad. Med. Nauk. SSSR
0(5):85-91 (1984)) as a result of selection for the metastasis character.
Tumor-Inhibiting Polypeptides
A number of polypeptides naturally produced by mammalian cells have been shown to have anti-tumor activity (i.e., inducing growth arrest, apoptosis and/or differentiation of cancer cells). For example, combinations of certain cytokines, such as interleukins and colony-stimulating factors, have been reported to induce terminal differentiation and concomitant growth arrest of particular types of tumor cells and cell lines (reviewed by Pimental, E., in:
Handbook of Growth Factors, Vol
. 1, Boca Raton, Fla.: CRC Press, pp. 28-34 (1994)). In addition, transforming growth factor &bgr; (TGF-&bgr;) and the interferons are known to be potent growth inhibitors for tumor cells under certain conditions in vivo and in vitro (Keski-Oja, J., and Moses, H. L.,
Med. Biol
. 66:13-20 (1987); Ohta, M., et al.,
Nature
329:539-541 (1987)). Other natural mammalian polypeptides having a variety of tumoricidal activities, such as the induction of apoptosis in certain tumor cells, include the tumor necrosis factors (TNFs) (reviewed by Pimental, E., in:
Handbook of Growth Factors, Vol
. 3, Boca Raton, Fla.: CRC Press, pp. 241-278 (1994)).
Recently, a family of TNF-related cytokines and their receptors with somewhat common structural features has been identified. This family includes the TNF, LT-&agr;, LT-&bgr;, Fas, CD27, CD40, OX-40, and nerve growth factor (NGF) receptor-ligand systems (Smith, C., et al.,
Cell
76:959-962 (1994); Armitage, R. J.,
Curr. Opin. Immunol
. 6:407-413 (1994)). With the exception of NGF, all of these TNF-related cytokines are thought to be involved in the regulation of the immune system. TNF and lymphotoxin-alpha (LT-&agr; or TNF-&bgr;) are related cytokines involved in many regulatory activities (Vassalli, P.,
Ann. Rev. Immunol
. 10:411-452 (1992); Paul, N., and Ruddle, N.,
Ann. Rev. Immunol
. 6:407-438 (1988)) but their roles in the immune system, while apparently critical, remain enigmatic (de Kossodo, S., et al,
J. Exp. Med
. 176:1259-1264 (1992)). TNF is synthesized in response to various insults by a variety of cell types; this is generally regarded as one of the primary events in the inflammatory cascade, including a potent antitumor effect on mice (Blankenstein, T., et al,
J. Exp. Med
173:1047-1052 (1991)). Activated macrophages are the major source of membrane-bound TNF, although it is also produced by activated lymphocytes and several other cell types. In contrast, LT-&agr; is produced specifically by lymphocytes and exists in membrane-associated form only via a trimeric complex with LT-&bgr; (Browning, J., et al.,
Cell
72:847-855 (1993)). LT-&bgr; shows a spectrum of activities similar to that of TNF in in vitro systems, but is less potent (Browning, J., and Ribolini, A.,
J. Immunol
. 143:1859-1867 (1989)). Both TNF and LT-&agr; induce apoptosis in various systems (Cohen, J. J., et al,
Ann. Rev. Immunol
. 10:267-293 (1992); Golstein, P., et al.,
Immunol. Rev
. 121:29-65 (1991); Sarin, A., et al.,
J. Immunol
. 155:3716-3718 (1995)). Recently, tumor growth inhibition mediated by LT-&agr; has been reported (Qin, Z., and Blankenstein, T.,
Cancer Res
. 55:4747-4751 (1995)).
TNF and LT-&agr; are also released by a number of tumor cells of various origins, such as mouse fibrosarcomas, human epithelial cell lines and T-cell leukemia cells and cell lines (Rubin, B. Y., et al.,
J. Exp. Med
. 164:1350-1355 (1986); Spriggs, D. R., et al,
J. Clin. Invest
. 81:455-460 (1988); Ishibashi, K., et al.,
Blood
77:2451-2455 (1991)). The genes encoding TNF, LT-&agr; and LT-&bgr; lie closely spaced within the class III region of the major histocompatibility complex (MHC) (Spies, T., et al.,
Proc. Natl. Acad. Sci. USA
83:8699-8702 (1986); Nedospasov, S. A., et al.,
Nucl. Acids Res
. 14:7713-7725 (1986); Gardner, S. M., et al.,
J. Immunol
. 139:476-483 (1987)). These genes are thought to be evolutionarily related and are though to have formed the locus by tandem gene duplications, although the opposite orientation of LT-&bgr; transcription suggests that more complex evolutionary events may have taken place. Recently, another novel TNF family member has been cloned and designated as TNF-related apoptosis-inducing ligand (TRAIL) (Wiley, S. R., et al.,
Immunity
3:673-682 (1995)).
BRIEF SUMMARY OF THE INVENTION
The present invention generally relates to tumor-inhibiting genes and polypeptides, and methods of treating cancers using these genes and polypeptides. Specifically, the invention provides isolated tag7 nucleic acid molecules comprising a polynucleotide having a nucleotide sequence at least about 65% (more preferably at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95% or at least about 99%) identical to a reference sequence selected from the group consisting of
(a) the nucleotide sequence set forth in SEQ ID NO:1:
(b) a nucleotide sequence encoding the tag7 polypeptide having the complete amino acid sequence set forth in SEQ ID NO:2;
(c) the nucleotide sequence encoding the mature tag7 polypeptide having the amino acid sequence at positions about 20-182 in SEQ ID NO:2;
(d) a nucleotide sequence of a polynucleotide which hybridizes under stringent conditions to a polynucleotide having the nucleotide sequence set forth in SEQ ID NO:1;
(e) a nucleotide sequence of a polynucleotide which hybridizes under defined conditions to a polynucleotide having the nucleotide sequence set forth in SEQ ID NO:1; and
(f) a nucleotide sequence complementary to any of the nucleotide sequences in (a), (b), (c), (d
Georgiev Georgii P.
Kiselev Sergei L.
Ostermann Elinborg
Prokhorchouk Egor B.
Bansal Geetha P.
Boehringer Ingelheim International GmbH
Huff Sheela
Sterne Kessler Goldstein & Fox P.L.L.C.
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