Human protein kinase and kinase inhibitors

Details Human protein kinase and kinase inhibitors Human protein kinase and kinase inhibitors

1997-11-25

2001-02-27

Wax, Robert A. (Department: 1652)

Chemistry: molecular biology and microbiology

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

Transferase other than ribonuclease

C435S069100, C435S252300, C435S320100, C435S069200, C435S015000, C435S006120, C536S023200, C536S023500, C530S350000, C514S04400A

Reexamination Certificate

active

06194186

ABSTRACT:

FIELD OF THE INVENTION
This invention relates to nucleic acid and amino acid sequences of a human protein kinase and kinase inhibitors and to the use of these sequences in the diagnosis, prevention, and treatment of cell proliferation, and immune and developmental disorders.
BACKGROUND OF THE INVENTION
Kinases regulate many different cell proliferation, differentiation, and signaling processes by adding phosphate groups to proteins. Uncontrolled signaling has been implicated in a variety of disease conditions including inflammation, cancer, arteriosclerosis, and psoriasis. Reversible protein phosphorylation is the main strategy for controlling activities of eukaryotic cells. It is estimated that more than 1000 of the 10,000 proteins active in a typical mammalian cell are phosphorylated. The high energy phosphate which drives activation is generally transferred from adenosine triphosphate molecules (ATP) to a particular protein by protein kinases and removed from that protein by protein phosphatases. Phosphorylation occurs in response to extracellular signals (hormones, neurotransmitters, growth and differentiation factors, etc), cell cycle checkpoints, and environmental or nutritional stresses and is roughly analogous to turning on a molecular switch. When the switch goes on, the appropriate protein kinase activates a metabolic enzyme, regulatory protein, receptor, cytoskeletal protein, ion channel or pump, or transcription factor.
Protein tyrosine kinases, PTKs, specifically phosphorylate tyrosine residues on their target proteins and may be divided into transmembrane, receptor PTKs, and nontransmembrane, non-receptor PTKs. Transmembrane protein-tyrosine kinases are receptors for most growth factors. Binding of growth factor to the receptor activates the transfer of a phosphate group from ATP to selected tyrosine side chains of the receptor and other specific proteins. Growth factors (GF) associated with receptor PTKs include: epidermal GF, platelet-derived GF, fibroblast GF, hepatocyte GF, insulin and insulin-like GFs, nerve GF, vascular endothelial GF, and macrophage colony stimulating factor.
Non-receptor PTKs lack transmembrane regions and, instead, form complexes with the intracellular regions of cell surface receptors. Some of the receptors that function through non-receptor PTKs include those for cytokines and hormones (growth hormone and prolactin) and antigen-specific receptors on the surface of T and B lymphocytes. The protein products of oncogenes and many growth-factor receptors have protein kinase activities that phosphorylate tyrosine.
Another family of kinases is the protein kinase C (PKC) family. Phosphorylation plays an essential role in regulating PKC. These enzymes transduce signals promoting phospholipid hydrolysis and are recruited to membranes upon the production of diacylglycerol and, for the conventional isoforms, increased Ca
2+
concentrations. Binding of these cofactors results in conformational change that removes an autoinhibitory (pseudo substrate) domain from the active site, thus promoting substrate binding and phosphorylation. Apoptosis of prostate epithelial cells is regulated by activators and inhibitors of the PKC family. The PKC family of serine/threonine kinases has been associated with signal transduction regulation cell growth and differentiation but has recently been associated with the regulation of cell death (Day, M. L. et al. (1994) Cell Growth & Differ. 5: 735-741)(Powell, C. T. et al. (1996) Cell Growth & Differ. 7: 419-428). Most PKC isozymes require the physiological activator diacylglycerol, which is derived from membrane phospholipids. Additionally, PKC activity also requires association with cellular membranes and/or cytoskeletal components to execute many of its physiological functions. PKC modulates signal transduction pathways that have been linked to both positive and negative regulation of the cell cycle and the initiation of apoptosis. An example of a PKC which is involved in the growth-inhibitory action of transforming growth factor-betal (TGF-betal) in PC3, a human prostate cancer cell line, is protein kinase K02B12 from
C. elegans.
RNA-activated protein kinase (PKR) is a serine/threonine protein kinase induced by interferon treatment and activated by double stranded RNAs. When PKR becomes autophosphorylated, it catalyzes phosphorylation of the alpha subunit of protein synthesis eukaryotic initiation factor 2 (eLF-2). Protein kinase inhibitors (PKI) have demonstrated potential for their use in the treatment of human cancers, in particular leukemia. (Lock, R. B. (1997) Cancer Chemother. Pharmacol. 39(5): 399-409) An example of a serine/threonine kinase inhibitor is the P58 PKR inhibitor (PKRI) from
B. taurus, a
504-amino acid hydrophilic protein. PKRI, expressed as a histidine fusion protein in
E. coli,
blocked both the autophosphorylation of PKR and phosphorylation of the alpha subunit of eLF-2. Western blot analysis showed that PKRI is present not only in bovine cells but also in human, monkey, and mouse cells, suggesting the protein is highly conserved. Another example of an inhibitor of protein kinase C is the protein kinase inhibitor from mouse, which acts as an inhibitor of cAMP-dependent protein kinase and protein kinase C.
The discovery of a new PK and PKI and the polynucleotides encoding them satisfies a need in the art by providing new compositions which are useful in the diagnosis, prevention, and treatment of diseases associated with cell proliferation, and in particular, cancer, immune responses, and development disorders.
SUMMARY OF THE INVENTION
The invention features a substantially purified human protein kinase (PK) comprising the amino acid sequence selected from the group consisting of SEQ ID NO:1.
The invention further provides a substantially purified variant of ABBR having at least 90% amino acid identity to the amino acid sequence of SEQ ID NO:1 or a fragment of SEQ ID NO:1. The invention also provides an isolated and purified polynucleotide sequence encoding the polypeptide comprising the amino acid sequence of SEQ ID NO:1 or a fragment of SEQ ID NO:1. The invention also includes an isolated and purified polynucleotide variant having at least 90% polynucleotide identity to the polynucleotide sequence encoding the polypeptide comprising the amino acid sequence of SEQ ID NO:1 or a fragment of SEQ ID NO:1.
Additionally, the invention provides a composition comprising a polynucleotide sequence encoding the polypeptide comprising the amino acid sequence of SEQ ID NO:1 or a fragment of SEQ ID NO:1. The invention further provides an isolated and purified polynucleotide sequence which hybridizes under stringent conditions to the polynucleotide sequence encoding the polypeptide comprising the amino acid sequence of SEQ ID NO:1 or a fragment of SEQ ID NO:1, as well as an isolated and purified polynucleotide sequence which is complementary to the polynucleotide sequence encoding the polypeptide comprising the amino acid sequence of SEQ ID NO:1 or a fragment of SEQ ID NO:1.
The invention also provides an isolated and purified polynucleotide sequence comprising SEQ ID NO:2 or a fragment of SEQ ID NO:2, and an isolated and purified polynucleotide variant having at least 90% polynucleotide identity to the polynucleotide sequence comprising SEQ ID NO:2 or a fragment of SEQ ID NO:2. The invention also provides an isolated and purified polynucleotide sequence which is complementary to the polynucleotide sequence comprising SEQ ID NO:2 or a fragment of SEQ ID NO:2.
The invention further provides an expression vector containing at least a fragment of the polynucleotide sequence encoding the polypeptide comprising the amino acid sequence of SEQ ID NO:1 or a fragment of SEQ ID NO:1. In another aspect, the expression vector is contained within a host cell.
The invention also provides a method for producing a polypeptide comprising the amino acid sequence of SEQ ID NO:1 or a fragment of SEQ ID NO:1, the method comprising the steps of: (a) culturing the host cell containing an expression vector containing a

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