KIAA0551 polynucleotides and polypeptides use

Details KIAA0551 polynucleotides and polypeptides use KIAA0551 polynucleotides and polypeptides use

1999-09-10

2001-08-21

Priebe, Scott D. (Department: 1632)

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

Organic compounds

Carbohydrates or derivatives

C536S023100, C435S320100, C435S325000, C435S069100

Reexamination Certificate

active

06277979

ABSTRACT:

FIELD OF THE INVENTION
This invention relates to new uses for polynucleotides and polypeptides encoded by them, to their use in therapy and in identifying compounds which may be agonists, antagonists and/or inhibitors which are potentially useful in therapy, to production of such polypeptides and polynucleotides, and to the identification of new full-length polynucleotides and polypeptides.
SUMMARY OF THE INVENTION
In one aspect, the invention relates to new uses of KIAA0551 polynucleotides and polypeptides (Nagase et al., 1998, DNA Res.5, 31-39. Genbank acc. no. AB01123). Such uses include the treatment and/or prophylaxis of neuropathies, neuropathic pain, inflammatory and chronic pain, neurodegenerative conditions such as Motor Neuron Disease, Parkinson's Disease, Alzheimer's Disease and other dementias, as well as neuronal degeneration resulting from ischemic events, including cerebral ischemia after cardiac arrest, stroke and multi-infarct dementia and also after cerebral ischemic events such as those resulting from surgery and/or during childbirth, hereinafter referred to as “the Diseases,” amongst others.
Thus according to one aspect of the invention there is provided a method of treatment or prophylaxis of a neurotraumatic disease. Neurotraumatic diseases/events as defined herein include both open or penetrating head trauma, such as caused by surgery, or a closed head trauma injury, such as caused by an injury to the head region. Also included within this definition is ischemic stroke, particularly to the brain area, transient ischemic attacks following coronary by-pass and cognitive decline following other transient ischemic conditions.
In another aspect the invention relates to KIAA0551 recombinant materials and methods for their production. In a further aspect, the invention relates to methods for identifying agonists and antagonists/inhibitors using the materials provided by the invention, and treating conditions associated with KIAA0551 imbalance with the identified compounds. In a still further aspect, the invention relates to diagnostic assays for detecting diseases associated with inappropriate KIAA0551 activity or levels. In a yet further aspect the invention relates to newly identified full-length KIAA0551 polynucleotides and to their use in therapy, diagnosis and methods for identifying antagonists and agonists.
DESCRIPTION OF THE INVENTION
In a first aspect, the present invention relates to the use of a compound selected from:
(a) a KIAA0551 polypeptide;
(b) a compound which activates a KIAA0551 polypeptide; or
(c) a compound which inhibits a KIAA0551 polypeptide; or
(d) a polynucleotide encoding a KIAA0551 polypeptide,
for the manufacture of a medicament for treating:
(i) neuropathies;
(ii) neuropathic pain;
(iii) inflammatory and chronic pain;
(iv) neurodegenerative conditions;
(v) neurotraumatic disease or ischaemic damage in cardiac tissues.
Such KIAA0551 polypeptides include isolated polypeptides comprising an amino acid sequence which has at least 95% identity, preferably at least 97-99% identity, to that of SEQ ID NO:2 over the entire length of SEQ ID NO:2. Such polypeptides include those comprising the amino acid sequence of SEQ ID NO:2.
Further polypeptides of the present invention include isolated polypeptides in which the amino acid sequence has at least 95% identity, preferably at least 97-99% identity, to the amino acid sequence of SEQ ID NO:2 over the entire length of SEQ ID NO:2. Such polypeptides include the polypeptide of SEQ ID NO:2.
Further peptides of the present invention include isolated polypeptides encoded by a polynucleotide comprising the sequence contained in SEQ ID NO: 1.
Such polypeptides are new and form part of the present invention.
Human KIAA0551 has been described as a partial cDNA sequence isolated from human brain (Nagase et al, 1998, DNA Res. 5, 31-39). This sequence encodes a polypeptide with no assigned function but with some predicted structural similarity to Sterile 20-family of protein kinases, in particular to murine NIK (Su et al., 1997, EMBO J. 16, pp.1279-1290).
Using standard differential display techniques as well as quantitative RT-PCR (TaqMan™) techniques, it has been shown that KIAA0551 mRNA is upregulated in dorsal root ganglia (DRGs) during rat sciatic neuropathy, a procedure accompanied by increased sensitivity to somatic pain (SEQ ID NO:3, SEQ ID NO: 5 and
FIGS. 1
a
and
b
). The polynuclcotide sequences SEQ ID NO:3 and SEQ ID NO:5 represent the partial rat KIAA0551 cDNA fragrnents isolated in the differential display. The amino acid sequence of SEQ ID NO:4 is the predicted polypeptide sequence encoded by the polynucleotide of SEQ ID NO:3. The full length human KIAA0551 cDNA has been cloned from a human foetal brain cDNA library using standard PCR and RACE-PCR techniques (Ausubel et al. (Ed.), Current Protocols in Molecular Biology, Vol. 2, John Wiley & Sons, (1996)). The polynucleotide sequence SEQ ID NO:1 represents full length human KIAA0551 cDNA. The amino acid sequence of SEQ ID NO:2 is the predicted polypeptide sequence encoded by the polynucleotide of SEQ ID NO:1. The full length KIAA0551 cDNA encodes 27 additional amino acids N-terminal to the published sequence which completes the kinase domain. Analysis of the full-length protein reveals a putative kinase domain (amino acid residues 25-289), two NIK-like domains (amino acid residues 290-506, 668-845) and a CNH domain (amino acid residues 1059-1309) of unidentified function. Using a ‘Prosite’ motif search, putative tyrosine phosphorylation sites at tyrosine residues 321, 323 and 446, putative cAMP/cGMP-dependent phosphorylation sites at serine residues 77, 259, 688, 915 and 1021 and threonine residues 87 and 827, as well as putative protein kinase C dependent phosphorylation sites at serine residues 255, 275, 528, 630, 755, 795, 968, 1104 and 1348 and threonine residues 124, 309, 349, and 819 have been identified.
Recombinant human NAK protein has been expressed in HEK293 cells and has been shown, upon isolation, to be protein of 190 kDa (FIG.
3
). Recombinant NAK protein displays enzymatic (kinase) activity, demonstrated by the ability of recombinant NAK protein to phosphorylate myelin basic protein (MBP) (
FIG. 4
a
). Furthermore, two C terminal truncates encoding amino acid residues 1-337 (NAK1-337) or 1-529 (NAK 1-529) display increased kinase activity (
FIG. 4
b
), defining a core catalytic region and suggesting an inhibitory role of the C-terminus of the protein and a putative mode of posttranslational enzymatic regulation.
Polypeptides of the present invention are believed to be members of the Sterile 20 (Ste20)-like protein kinase family of polypeptides (Fanger et al., 1997, Curr. Op. Genet. Dev. 7, 67-74), and show most homology to murine NIK (Su et al., 1997, FMBO J. 16, pp.1279-1290). They are therefore of interest because:
i) such proteins have been shown to act as activators of the Stress-activated protein kinase (SAPK) pathways, which have been implicated in the regulation of apoptotic cell death in neuronal cells and tissues (Fanger et al., 1997, Curr. Op. Genet. Dev. 7, 67-74);
ii) such proteins have been shown to act as activators of the NF-&kgr;B pathway, which has been implicated in inflammation control (Malinin et al, Nature 385, pp. 540-544 (1997); Mercurio and Manning, Curr. Op. Cell Biol. 11, pp. 226-232 (1999); Bacuerle, Cell 95, pp.729-731 (1998); Yin et al., Nature 396, pp.77-80 (1998));
iii) KIAA0551 mRNA is expressed broadly in human CNS (FIG.
2
); and
iv) the mRNA of the rat ortholog of KIAA0551 is upregulated during rat sciatic neuropathy, a procedure accompanied by increased sensitivity to somatic pain (SEQ ID NO:3, SEQ ID NO: 5 and
FIGS. 1
a
and
b
).
These properties are hereinafter referred to as “KIAA0551 activity” or “KIAA0551 polypeptide activity” or “biological activity of KIAA055 1”. Also included amongst these activities are antigenic and immunogenic activities of said KIAA0551 polypeptides, in particular the antigenic and immunogenic activities of the polypeptide of SEQ ID NO:2. Preferabl

Affiliated with

Also associated with

Rating

KIAA0551 polynucleotides and polypeptides use does not yet have a rating. At this time, there are no reviews or comments for this patent.

If you have personal experience with KIAA0551 polynucleotides and polypeptides use, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and KIAA0551 polynucleotides and polypeptides use will most certainly appreciate the feedback.

Rate now

Comments { 0 }

Profile ID: LFUS-PAI-O-2537234