MSP-18 protein and nucleic acid molecules and uses therefor

Details MSP-18 protein and nucleic acid molecules and uses therefor MSP-18 protein and nucleic acid molecules and uses therefor

2000-10-31

2002-05-21

Prouty, Rebecca E. (Department: 1652)

Chemistry: molecular biology and microbiology

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

Oxidoreductase

C435S190000, C435S193000, C435S069100, C435S320100, C435S006120, C435S325000, C435S252300, C530S350000

Reexamination Certificate

active

06391602

ABSTRACT:

BACKGROUND OF THE INVENTION
Lysyl oxidase is an extracellular copper enzyme that initiates the crosslinking of collagens and elastin by catalyzing oxidative deamination of the &egr;-amino group in certain lysine and hydroxylysine residues of collagens and lysine residues of elastin (Kaman in
Biology of Extracellular Matrix
, ed. Mecham (1986) Academic Press pp. 321-389). Lysyl oxidase has been shown to be important in a variety of cellular and physiologic processes including biogenesis of connective tissue matrices and bone resorption. A deficiency in lysyl oxidase activity is found in two X-linked, recessively inherited connective tissue disorders, the type IX variant of the Ehlers-Danlos syndrome and the Menkes syndrome, and in the X-linked, recessively inherited mottled series of allelic mutant mice (all characterized by abnormalities in copper metabolism). (Byers et al. (1980)
New Engl. J. Med
. 303:61-65; Royce et al. (1980)
Biochemistry J
. 192:579-586; Kuivaniemi et al. (1982)
J. Clin. Invest
. 69:730-733; Kuivaniemi et al. (1985) Amer. J. Human. Genet. 37:798-808; Peltonen et al. (1983)
Biochemistry
22:6156-6163; Rowe et al. (1977)
J. Biol. Chem
. 252:939-942; Starcher et al. (1977)
Biochem. Biophys. Res. Commun
. 78:706-712; Danks in
The Metabolic Basis oflnherited Disease
”, eds. Stanbury et al. (1983), McGraw-Hill pp. 1251-1268). Increased lysyl oxidase activity has been associated with fibrotic disorders such as atherosclerosis, hypertension, and liver and pulmonary fibrosis. (Kagan, supra).
More recently there have been identified proteins having structural and/or functional similarities to lysyl oxidase. For example, a lysyl oxidase-like protein, referred to herein as “LOL”, was identified from a human skin fibroblast cDNA library that contains extensive homology to several coding domains within the human lysyl oxidase mRNA which is believed to be involved in collagen maturation. (Kenyon et al. (1993)
J. Biol. Chem
. 268:18435-18437 and Kim et al. (1995)
J. Biol. Chem
. 270:7176-7182). Likewise, a protein referred to herein as lysyl-oxidase related protein (“Lor”) has been identified which inhibits many of the structural features of lysyl oxidase and is overexpressed in senescent fibroblasts and is believed to play a role in age-associated changes in extracellular proteins. (Saito et al. (1997)
J. Biol. Chem
. 272:8157-8160). Lor contains four domains referred to herein as scavenger receptor cysteine-rich domains (“SRCR domains”) which are believed to be involved in binding to other cell surface proteins or extracellular molecules. The SRCR domain joins a long list of other widely distributed cysteine-containing domains found in extracellular portions of membrane proteins and in secreted proteins (Doolittle (1985)
Trends Biochem. Sci
. 10:233-237; Krieger in
Molecular Structures of Receptors
, eds. Rossow et al. (1986) Horwood, Chichester, U.K. pp. 210-231). Examples include the EGF-like domain, immunoglobulin superfamily domains, the LDL receptor/complement. C9 domain, clotting factor Kringle domains, and fibronectin domains. These disulfide cross-linked domains appear to provide stable core structures that (i) are able to withstand the rigors of the extracellular environment; (ii) are well suited for a variety of biochemical tasks, often involving binding; and (iii) are readily juxtaposed to other types of domains to permit the construction of complex mosaic proteins. (Doolittle supra; Sudhof et al. (1985)
Science
228:815-822). Lastly, a mouse cDNA encoding a putative protein having sequence homology to lysyl oxidase has recently been identified having the Accession No. AF053368, referred to herein as “Lor-2”.
A greater understanding of the role which lysyl oxidase-like as well as SCRC domain containing proteins play in various disorders would lead to the determination of highly specific drug targets which would work to treat these disorders, e.g., cardiovascular disorders, a disorder arising from altered lysyl oxidase-like activity or a disorder arising from improperly regulated SRCR-domain containing protein activity giving rise to improperly regulated cellular processes.
SUMMARY OF THE INVENTION
The present invention is based, at least in part, on the discovery of novel nucleic acid molecules and proteins encoded by such nucleic acid molecules, referred herein as Myocardium Secreted Protein-18 (“MSP-18”) molecules. The MSP-18 nucleic acid and protein molecules of the present invention are useful as modulating agents in regulating a variety of cellular processes in the cardiovascular system, e.g., cardiac cellular processes. Accordingly, in one aspect, this invention provides isolated nucleic acid molecules encoding MSP-18 proteins or portions thereof, as well as nucleic acid fragments suitable as primers or hybridization probes for the detection of MSP-18-encoding nucleic acids. In another embodiment, an isolated nucleic acid molecule of the present invention preferably encodes a MSP-18 protein which includes a signal sequence and/or is secreted. In yet another embodiment, an isolated nucleic acid molecule of the present invention preferably encodes a MSP-18 protein which lacks a signal sequence and/or is intracellular.
In one embodiment, a MSP-18 nucleic acid molecule of the invention is at least 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96% 97%, 98%, 99%, or more homologous to a nucleic acid sequence (e.g., to the entire length of the nucleotide sequence) having the nucleotide sequence shown in SEQ ID NO:1 or a complement thereof.
In a preferred embodiment, the isolated nucleic acid molecule includes the nucleotide sequence shown in SEQ ID NO:1, or a complement thereof. In another embodiment, the nucleic acid molecule includes nucleotides 143-2401 shown in SEQ ID NO:1. In another preferred embodiment, the nucleic acid molecule has the nucleotide sequence shown in SEQ ID NO:1. In another preferred embodiment, the nucleic acid molecule comprises a fragment of at least 50 contiguous nucleotides of the nucleotide sequence shown in SEQ ID NO:1, or a complement thereof.
In another embodiment, an MSP-18 nucleic acid molecule includes a nucleotide sequence encoding a protein having an amino acid sequence at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or more homologous to the amino acid sequence shown in SEQ ID NO:2.
In another preferred embodiment, an isolated nucleic acid molecule encodes the amino acid sequence of human MSP-18. In yet another preferred embodiment, the nucleic acid molecule includes a nucleotide sequence encoding a protein having the amino acid sequence shown in SEQ ID NO:2. In yet another preferred embodiment, the nucleic acid molecule includes a nucleotide sequence encoding a protein at least 753 amino acids in length. In yet another preferred embodiment, the nucleic acid molecule includes a nucleotide sequence encoding a protein at least 728 amino acids in length. In a further preferred embodiment, the nucleic acid molecule encodes a protein having an MSP-18 activity (as described herein).
Another embodiment of the invention features nucleic acid molecules, preferably MSP-18 nucleic acid molecules, which specifically detect MSP-18 nucleic acid molecules relative to nucleic acid molecules encoding non-MSP-18 proteins. For example, in one embodiment, such a nucleic acid molecule is at least 300, 400, 500, 600, 650, 700, 750, or 753 nucleotides in length and hybridizes under stringent conditions to a nucleic acid molecule comprising the nucleotide sequence shown in SEQ ID NO:1, or a complement thereof. In a particularly preferred embodiment, the nucleic acid molecule comprises a fragment of at least 50 contiguous nucleotides of the nucleotide sequence of SEQ ID NO:1, SEQ ID NO:3, or a complement thereof. In another preferred embodiment, the nucleic acid molecules are at least 25, 50, 75, 100, 150, 200, 250 or more nucleotides (e.g., contiguous) in length and hybridize under stringent conditions to SEQ ID NO:1. In other preferred embodiments, the nucleic acid molecule e

Affiliated with

Also associated with

Rating

MSP-18 protein and nucleic acid molecules and uses therefor does not yet have a rating. At this time, there are no reviews or comments for this patent.

If you have personal experience with MSP-18 protein and nucleic acid molecules and uses therefor, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and MSP-18 protein and nucleic acid molecules and uses therefor will most certainly appreciate the feedback.

Rate now

Comments { 0 }

Profile ID: LFUS-PAI-O-2817246