Nucleic acids encoding human tissue factor inhibitor

Details Nucleic acids encoding human tissue factor inhibitor Nucleic acids encoding human tissue factor inhibitor

2003-03-04

2004-10-19

Mertz, Prema (Department: 1646)

Organic compounds -- part of the class 532-570 series

Organic compounds

Carbohydrates or derivatives

C436S069000, C530S350000

Reexamination Certificate

active

06806360

ABSTRACT:

BACKGROUND OF THE INVENTION
This invention relates to a coagulation inhibitor known as tissue factor inhibitor (TFI) and alternatively as lipoprotein associated coagulation inhibitor (LACI). More particularly, the invention relates to a cDNA clone representing essentially the full size TFI.
The coagulation cascade that occurs in mammalian blood comprises two distinct systems—the so-called intrinsic and extrinsic systems. The latter system is activated by exposure of blood to tissue thromboplastin (Factor III), hereinafter referred to as tissue factor (TF). Tissue factor is a lipoprotein that arises in the plasma membrane of many cell types and in which the brain and lung are particularly rich. Upon coming into contact with TF, plasma Factor VII or its activated form, Factor VII
a
, forms a calcium-dependent complex with TF and then proteolytically activates Factor X to Factor X
a
, and Factor IX to Factor IX
a
.
Early studies concerning the regulation of TF-initiated coagulation showed that incubation of TF (in crude tissue thromboplastin preparations) with serum inhibited its activity in vitro and prevented its lethal effect when it was infused into mice. Extensive studies by Hjort,
Scand. J. Clin. Lab. Invest
. 9, Suppl. 27, 76-97 (1957), confirmed and extended previous work in the area, and led to the conclusion that an inhibitory moiety in serum recognized the Factor VII-TF complex. Consistent with this hypothesis are the facts that the inhibition of TF that occurs in plasma requires the presence of Ca
2+
(which is also necessary for the binding of Factor VII/VII
a
to TF) and that inhibition can be prevented and/or reversed by chelation of divalent cations with EDTA. More recent investigations have shown that not only Factor VII
a
but also catalytically active Factor X
a
and an additional factor are required for the generation of TF inhibition in plasma or serum. See Broze and Miletich,
Blood
69, 150-155 (1987), and Sanders et al.,
Ibid
., 66, 204-212 (1985). This additional factor, defined herein as tissue factor inhibitor (TFI), and alternatively as lipoprotein associated coagulation inhibitor (LACI), is present in barium-absorbed plasma and appears to be associated with lipoproteins, since TFI functional activity segregates with the lipoprotein fraction that floats when serum is centrifuged at a density of 1.21 g/cm
3
. According to Broze and Miletich, supra, and
Proc. Natl. Acad. Sci. USA
84, 1886-1890 (1987), HepG2 cells (a human hepatoma cell line) secrete an inhibitory moiety with the same characteristics as the TFI present in plasma.
In copending application Ser. No. 77,366, filed Jul. 23, 1987, a purified tissue factor inhibitor (TFI) is disclosed which was secreted from HepG2 cells. It was found to exist in two forms, a TFI
1
, migrating at about 37-40,000 daltons and a TFI
2
at about 25-26,000 daltons, as determined by sodium dodecylsulfate polyacrylamide gel electrophoresis (SDS-PAGE). A partial N-terminal amino acid sequence for the TFI was assigned as:
1
X-X-Glu-Glu-Asp-Glu-Glu-His-Thr-Ile-Ile-Thr-Asp-

     15  16
Thr-Glu-Leu-Pro-Pro-Leu-Lys-Leu-Met-His-Ser-Phe-

       27
(Phe)-Ala
wherein X—X had not been determined. The disclosure of said application is incorporated herein by reference.


REFERENCES:
patent: 4966852 (1990-10-01), Wun et al.
U.S. patent application Ser. No. 07/077,366, Broze et al., filed Jul. 23, 1987.
Hjort, Scan, J. Clin. Lab. Invest. 9 (supp. 27), p. 76-97 (1957).
Broze et al, Blood 69, 150-155 (1987).
Sanders et al, Blood 66, 204-212 (1985).
Broze et al, Proc. Natl. Acad. Sci, USA 84, 1886-1890 (1987).
Proudfoot et al, Nature, 252, 359-362 (1981).
Von Heijne, Eur. J. Biochem, 123, 17-21 (1983).
Von Heijne, J. Mol. Biol. 184, 99-105 (1985).
Kozak, Cell, 44, 283-292 (1986).
Henikoff, Gene, 28, 351-359 (1984).
Lipman et al, Science 227, 1435-1441 (1985).
Sanger et al, Proc. Natl. Acad. Sci. USA 70(4), 1209-1213 (1973).
Maniatis et al, Molecular Cloning: A Laboratory Manual, Cold Spring Harbor Laboratory, Cold Spring Harbor, New York (1982).
Thomas, Methods Enzymol. 100, 255-266 (1983).
Lizardi & Engelberg, Anal. Biochem. 98, 116-122 (1979).
Wun et al, FEBS Lett. 1, 11-16 (1987).
Kidera et al, J. Prot. Chem. 4, 23-55 (1985).
Young et al, Proc. Natl. Acad. Sci. USA, 80, 1194-1198 (1983).

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