Apoptosis-inducing protein and gene encoding the same

Details Apoptosis-inducing protein and gene encoding the same Apoptosis-inducing protein and gene encoding the same

1998-10-19

2001-02-27

Prouty, Rebecca E. (Department: 1633)

Chemistry: molecular biology and microbiology

Enzyme , proenzyme; compositions thereof; process for...

Transferase other than ribonuclease

C435S320100, C435S325000, C435S252300, C435S254200, C435S348000, C435S365000, C435S357000, C435S358000, C435S352000, C424S094500, C536S023200, C514S04400A

Reexamination Certificate

active

06194187

ABSTRACT:

BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to a protein which induces apoptosis (cell death), a gene encoding the same, and a therapeutic agent for malignant tumors.
2. Background Art
The mitogen-activated protein (MAP) kinase signaling cascade, a signal transduction pathway well conserved in cells from yeasts to vertebrates, consists of three distinct members of the protein kinase family, including MAP kinase (MAPK), MAPK kinase (MAPKK), and MAPKK kinase (MAPKKK) (T. Sturgill & J. Wu, Biochim. Biophys. Acta. 1092, 350, 1991; E. Nishida & Y. Gotoh, Trends Biochem. Sci., 18, 128, 1993; B. Errede & D. Levin, Curr. Opin. Cell Biol., 5, 254, 1993; C. Marshall, Curr. Opin. Genet. Dev., 4, 82, 1994). MAPKKK phosphorylates and thereby activates MAPKK, and the activated form of MAPKK in turn phosphorylates and activates MAPK. Activated MAPK translocates to the cell nucleus and regulates the activities of transcription factors and thereby controls expression of various genes (T. Sturgill & J. Wu, Biochim. Biophys. Acta, 1092, 350, 1991; E. Nishida & Y. Gotoh, Trends Biochem. Sci., 18, 128, 1993; B. Errede & D. Levin, Curr. Opin. Cell Biol., 5, 254, 1993; C. Marshall, Curr. Opin. Genet. Dev., 4, 82, 1994).
Recent studies on MAPK signal transduction pathways have shown that at least two distinct MAPKKK-MAPKK-MAPK signal transduction pathways function in mammalian cells (R. Davis, Trends Biochem. Sci., 19, 470, 1994; A. Waskiewicz & J. Cooper, Curr. Opin. Cell Biol., 7, 798, 1995; J. Kyriakis & J. Avruch, J. Biol. Chem., 265, 17355, 1990; B. Derijard et al., Cell, 76, 1025, 1994; M. Yan et al., Nature, 372, 798, 1994; K. Yamaguchi et al., Science, 270, 2008, 1995; J. Kyriakis et al., Nature, 369, 156, 1994; I. Sanchez et al., Nature, 372, 794, 1994; B.
Derijard et al. Science, 267, 682, 1995; S. Matsuda et al., J.
Biol. Chem., 270, 12781, 1995). These two pathways each consist of the Raf-MAPKK-MAPK pathway and the MEKK-SEK1 (or MKK4)-SAPK (or JNK) pathway.
MKK3/MAPKK6 (or MKK6, a close relative of MKK3) and p38 protein kinase are protein kinases corresponding to MAPKK and MAPK, respectively, and are known to form another MAPK signal transduction pathway (R. Davis, Trends Biochem. Sci., 19, 470, 1994; A. Waskiewicz & J. Cooper, Curr. Opin. Cell Biol., 7, 798, 1995; J. Han et al., J. Biol. Chem., 271, 2886, 1996; J. Raingeaud et al., Mol. Cell. Biol., 16, 1247, 1996; T. Moriguchi et al., J. Biol. Chem., 271, 13675, 1996).
Recent studies suggest that the SAPK and/or p38 MAP kinase signaling cascades are involved in at least a part of the signal transduction pathways which induce apoptosis (Z. Xia et al., Science, 270, 1326, 1995; Y. -R. Chen et al., J. Biol. Chem., 271, 631, 1996; N. Johnson et al., J. Biol. Chem., 271, 3229, 1996; M. Verheij et al., Nature, 380, 75, 1996). Apoptosis herein means cell death different from necrosis, namely program cell death. In apoptosis, DNA in each nucleosome is fragmented and the fragmented DNAs can be observed like a ladder by electrophoresis. Furthermore, apoptosis is considered to be involved in autoimmune diseases, HIV infection, neurotic diseases, hepatitis, leukemia, renal diseases, skin diseases, eye diseases and aging as well as cancer degeneration (“Forefront of Research on Apoptosis.” Ed. Masayuki Miura, Shigenobu Toya and Sadatoshi Kizaki, Experimental Medicine, Vol. 13, 1995).
Tumor necrosis factor-&agr; (TNF-&agr;) is known to be a strong cellular apoptosis initiation substance. A recent study has shown that such cellular apoptosis initiation substances activate the SAPK signal transduction system (J. Kyriakis et al., Nature, 372, 794, 1994; J. Raingeaud et al., J. Biol. Chem., 270, 7420, 1995).
However, as far as the inventors know, proteins corresponding to MAPKKK present in upstream of the MKK3-p38 pathway and the SEK1-SAPK pathway, mechanisms of activation of these pathways, and mechanisms of apoptosis through these pathways have not been reprted.
SUMMARY OF THE INVENTION
The inventors have now identified a novel mammalian protein (ASK1) corresponding to MAPKKK, which activates the MKK3-p38 signal transduction pathway as well as the SEK1-SAPK signal transduction pathway. The inventors have also found that proinflammatory cytokines activate ASK1 and the activated ASK1 is involved in cellular induction of apoptosis through the SEK1-SAPK and MKK3-p38 signaling cascades. Furthermore, the inventors found that a dominant-negative mutant of ASK1 inhibits apoptosis induced by TNF-&agr;. The present invention is based on these findings.
Accordingly, an object of the present invention is to provide a protein which induces apoptosis, a base sequence encoding the protein, a vector comprising the base sequence, a host comprising the vector and a method for producing the protein.
Another object of the present invention is to provide an agent for use in the treatment of malignant tumors or a gene therapy agent for use in the treatment of malignant tumors.
A further object of the present invention is to provide a partial peptide of the apoptosis-inducing protein and an antibody against the apoptosis-inducing protein.
The protein according to the present invention is a protein which has a protein kinase activity and enhances the SEK1 kinase activity and/or MKK3 kinase activity, or derivatives thereof.


REFERENCES:
Genbank-est111 Database, accession No. T78387, Mar. 1995.
Tibbles et al., EMBO J., 15(24), 7026-7035, Aug. 1996.
Rana et al., J.B.C., 271(32), 19025-19028, Aug. 1996.
Wang et al., “Molecular Cloning and Characterization of a Novel Protien Kinase with a Catalytic Domain Homologous to Mitogen-activated Protein Kinase Kinase*”, The Journal of Biological Chemistry, vol. 271, No. 49, pp. 31607-31611, Dec. 6, 1996.
Hidenori Ichijo et al., “Induction of Apoptosis by Ask1, a Mammalian MAPKKK that Activates SAPK/JNK and p38 Signaling Pathways”, This week In Science, vol. 275, Jan. 3, 1997, pp. 90-94.
Blank et al., “Molecular Cloning of Mitogen-activated Protien/ERK Kinases (MEKK) 2 and 3”, The Journal of Biological Chemistry, vol. 271, No. 10, pp. 5361-5368, Mar. 8, 1996.

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