Chemistry: natural resins or derivatives; peptides or proteins; – Proteins – i.e. – more than 100 amino acid residues
Patent
1994-04-22
1996-11-26
Walsh, Stephen G.
Chemistry: natural resins or derivatives; peptides or proteins;
Proteins, i.e., more than 100 amino acid residues
530395, C07K 1447, C07K 1471
Patent
active
055787037
DESCRIPTION:
BRIEF SUMMARY
FIELD OF THE INVENTION
This invention relates to protein biochemistry. More particularly, it relates to molecules which bind to the substance known as transforming growth factor-.beta.1 ("TGF-.beta.1" hereafter). The invention also relates to nucleic acid sequences coding for the molecule, and uses thereof.
BACKGROUND AND PRIOR ART
A family of molecules is referred to as the "TGF-.beta.s". These are 25 kd dimeric proteins which have multi-functional effects on growth and differentiation of cells, both in vitro and in vivo. See Roberts et al. in Peptide Growth Factors And Their Receptors I (Sporn et al., eds., pp 419-472; Springer-Verlag, Berlin, 1990); Moses et al., Cell 63: 245-247 (1990); Massague, Ann. Rev. Cell. Biol. 6: 597-641 (1990). The family contains at least three different, structurally related members, identified as ".beta.1, .beta.2 and .beta.3". Many other proteins are more distantly related, including bone morphogenic proteins, Mullerian inhibitory substance, activins, inhibins, and so forth.
Originally, the TGF-.beta. family of proteins was identified as being involved in increasing anchorage independent growth of normal rat kidney cells; however, the proteins are also recognized as a potent growth inhibitor for diverse cell types, including hematopoietic cells, lymphocytes, epithelial and endothelial cells (Ohta et al., Nature 329: 539-541 (1987); Kehri et al., J. Immunol 137: 3855-3860 (1986); Moses et al., in Cancer Cells 3 (Feramisco et al., ed; Cold Spring Harbor, N.Y., 1985); pg. 65-71; Baird et al.. Biochem. Biophys. Res. Commun 138: 476-482 (1986); Frater-Schroder et al., Biochem. Biophys. Res. Commun. 137: 295-302 (1986); Heimark et al., Science 233: 1078-1080 (1986)). The molecules have a dramatic effect on accumulation of extracellular matrix proteins (Massague, supra), and have been implicated in pathogenesis glomerulonephritis (Border et al., Nature 346: 371-374 (1990)); liver cirrhosis (Castilia et al., N. Eng. J. Med. 324: 933-940 (1990)); and pulmonary fibrosis (Khalil et al., in Clinical Application of TGF-.beta.1 (Bocket al., ed. Ciba Foundation Symposium 157, John Willy & Sons, 1991, pg. 194-211).
The TGF-.beta. family interacts with other proteins on several levels. One of these is mediation of binding via cell surface receptors. The art recognizes three distinct high affinity receptors for TGF-.beta.s, referred to as types I, II and III. The first two of these have molecular masses of 53 and 70-85 kd, respectively, while the third is denoted "betaglycan" because of its proteoglycan like structure, and is further characterized by a molecular mass of 200-400 kd. Massague et al., in Transforming Growth Factor-.beta.s: Chemistry, Biology and Therapeutics (Piez et al., eds., Ann. N.Y. Acad. Sci. 593, 1990), pg. 59-72; Segarini et al., in Clinical Applications of TGF-.beta. (Bock et al., eds. Ciba Foundation Symposium 157, John Wiley & Sons, 1991, pg 29-50). The betaglycan molecule is a membrane proteoglycan, having a 100-140 kd core protein with unknown functional importance, while type I and II receptors appear to be involved in transduction of TGF-.beta. cellular effect. Segarini et al., J. Biol. Chem. 263: 8366-8370 (1988); Cheifetz et al., J. Biol. Chem. 263: 16884-16991 (1988); Massague et al., supra. Some cell lines express only type I receptors and are inhibited by TGF-.beta.1. These include hematopoietic progenitor cell lines (Ohta et al., supra) and squamous cancer cell lines (Ichiyo et al., Exp. Cell Res. 187: 263-269 (1990)). Mutant cell lines of mink epithelial cells have been shown to have lost or to have anomalous expression of type I and/or type II receptors (Boyd et al., J. Biol. Chem. 264: 2272-2278 (1989); Laiho et al., J. Biol. Chem. 265: 18518-18524 (1990)).
Additional binding molecules for TGF-.beta. having molecular masses of 60 kd, 85-320 kd, and 400 kd have been reported in pituitary tumor cell lines, rat glomeruli, and bovine liver cells, respectively, as reported by Cheifetz et al., J. Biol. Chem. 263: 17225-17228 (1988); Mackay et al., J. Biol
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Heldin Carl-Hendrik
Hellman Ulf
Ichijo Hidenori
Miyazono Kohei
Ronnstrand Lars
Ludwig Institute for Cancer Research
Walsh Stephen G.
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