Chemistry: molecular biology and microbiology – Vector – per se
Patent
1997-02-11
1998-11-17
Campell, Bruce R.
Chemistry: molecular biology and microbiology
Vector, per se
536 235, 935 10, C12N 1500, C07H 2102
Patent
active
058375236
DESCRIPTION:
BRIEF SUMMARY
FIELD OF THE INVENTION
The present invention relates to proteins which lack tyrosine kinase activity and dimerize with epidermal growth factor receptor and/or p185, to nucleic acid molecules that encode such proteins, to pharmaceutical compositions that comprise such nucleic acid molecules in combination with delivery vehicles which facilitate transfer of the nucleic acid molecule to a cell, and to methods of preventing tumors and treating individuals having tumors by administering such pharmaceutical compositions.
BACKGROUND OF THE INVENTION
The rat cellular protooncogene c-neu and its human counterpart c-erbB2 encode 185 kDa transmembrane glycoproteins termed p185. Tyrosine kinase (tk) activity has been linked to expression of the transforming phenotype of oncogenic p185 (Bargmann et al., Proc. Natl. Acad. Sci. U.S.A., 1988, 85, 5394; and Stern et al., Mol. Cell. Biol., 1988, 8, 3969, each of which is incorporated herein by reference). Oncogenic neu was initially identified in rat neuroglioblastomas (Schechter et al., Nature, 1984, 312, 513, which is incorporated herein by reference) and was found to be activated by a carcinogen-induced point mutation generating a single amino acid substitution, a Val to Glu substitution at position 664, in the transmembrane region of the transforming protein (Bargmann et al., Cell, 1986, 45, 649, which is incorporated herein by reference). This alteration results in constitutive activity of its intrinsic kinase and in malignant transformation of cells (Bargmann et al., EMBO J., 1988, 7, 2043, which is incorporated herein by reference). The activation of the oncogenic p185 protein tyrosine kinase appears to be related to a shift in the molecular equilibrium from monomeric to dimeric forms (Weiner et al., Nature, 1989, 339, 230, which is incorporated herein by reference).
Overexpression of c-neu or c-erbB2 to levels 100-fold higher than normal (i.e., >10.sup.6 receptors/cell) also results in the transformation of NIH3T3 cells (Chazin et al., Oncogene, 1992, 7, 1859; DiFiore et al., Science, 1987, 237, 178; and DiMarco et al., Mol. Cell. Biol., 1990, 10, 3247, each of which is incorporated herein by reference). However, NIH3T3 cells or NR6 cells which express cellular p185 at the level of 10.sup.5 receptors/cell are not transformed (Hung et al., Proc. Natl. Acad. Sci. U.S.A., 1989, 86, 2545; and Kokai et al., Cell, 1989, 58, 287, each of which is incorporated herein by reference), unless co-expressed with epidermal growth factor receptor (EGFR), a homologous tyrosine kinase (Kokai et al., Cell, 1989, 58, 287, which is incorporated herein by reference). Thus, cellular p185 and oncogenic p185 may both result in the transformation of cells.
Cellular p185 is highly homologous with EGFR (Schechter et al., Nature, 1984, 312, 513; and Yamamoto et al., Nature, 1986, 319, 230, each of which is incorporated herein by reference) but nonetheless is distinct. Numerous studies indicate that EGFR and cellular p185 are able to interact (Stern et al., Mol. Cell. Biol., 1988, 8, 3969; King et al., EMBO J., 1988, 7, 1647; Kokai et al., Proc. Natl. Acad. Sci. U.S.A., 1988, 85, 5389; and Dougall et al., J. Cell. Biochem., 1993, 53, 61; each of which is incorporated herein by reference). The intermolecular association of EGFR and cellular p185 appear to up-regulate EGFR function (Wada et al., Cell, 1990, 61, 1339, which is incorporated herein by reference). In addition, heterodimers which form active kinase complexes both in vivo and in vitro can be detected (Qian et al., Proc. Natl. Acad. Sci. U.S.A., 1992, 89, 1330, which is incorporated herein by reference).
We have recently demonstrated that cellular rat p185 devoid of kinase activity due to either a single amino acid substitution in the consensus sequence for ATP binding, N757, or due to a cytoplasmic domain deletion, N691stop, was able to undergo EGF-induced heterodimerization with EGFR in living cells. EGF was also able to stimulate the transphosphorylation of N757 via EGFR. However, heterodimers composed of EGFR and certain trunc
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Greene Mark I.
Qian Xiaolan
Campell Bruce R.
The Trustees of the University of Pennsylvania
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