Smithkline Beecham Corporation

Sanjay Kumar

Peter R Young

George P Livi

Michael W Lark

Megan McHale McLaughlin

Marion M Van Horn

p38beta2 polypeptides and polynucleotides and methods for producing such polypeptides by recombinant techniques are disclosed. Also disclosed are methods for utilizing p38beta2 polypeptides and polynucleotides in the design of protocols for the treatment of central nervous system disorder such as senile dementia of the Alzheimer's type (SDAT), mutiple sclerosis, cerebral malaria, stroke, head trauma and spinal cord injury; cardiovascular diseases such as restenosis and atherosclerosis; inflammatory diseases such as Adult Respiratory Disease Syndrome (ARDS), Rheumatoid arthritis, Osteoarthritis, Inflammatory Bowel Disease (IBD), psoriasis, derratitis, asthma; and other such diseases or conditions associated with dysregulated or excess cytokines such as osteoporosis, sepsis due to surgical or traumatic incident, chronic renal failure, AIDs, cachexia and autoimmune conditions such as lupus erthyromatosis, host graft rejection and graft verus host disease, among others, and diagnostic assays for such conditions.

DNA encoding a novel homolog of CSBP/p38 MAP kinase

p38beta2 polypeptides and polynucleotides and methods for producing such polypeptides by recombinant techniques are disclosed. Also disclosed are methods for utilizing p38beta2 polypeptides and polynucleotides in the design of protocols for the treatment of central nervous system disorder such as senile dementia of the Alzheimer's type (SDAT), multiple sclerosis, cerebral malaria, stroke, head trauma and spinal cord injury; cardiovascular diseases such as restenosis and atherosclerosis; inflammatory diseases such as Adult Respiratory Disease Syndrome (ARDS), Rheumatoid arthritis, Osteoarthritis, Inflammatory Bowel Disease (IBD), psoriasis, dermatitis, asthma; and other such diseases or conditions associated with dysregulated or excess cytokines such as osteporosis, sepsis due to surgical or traumatic incident, chronic renal failure, AIDs, cachexia and autoimmune conditions such as lupus erthyromatosis, host graft rejection and graft versus host disease, among others, and diagnostic assays for such conditions.

Cytokine suppressive anti-inflammatory drug binding protein

ppGaNTase-T6 polypeptides and polynucleotides and methods for producing such polypeptides by recombinant techniques are disclosed. Also disclosed are methods for utilizing ppGaNTase-T6 polypeptides and polynucleotides in diagnostic assays.

ppGaNTase-T6

CSBP/p38 is a MAP kinase that is activated in response to stress, endotoxin, interleukin 1 and tumor necrosis factor. Using a catalytically inactive mutant (D168A) of human CSBP2 as the bait in a yeast two-hybrid screen, a kinase has been cloned which shares &tilde;70% amino acid identity to MAPKAP kinase-2, and thus was designated MAPKAP kinase-3. The binding of CSBP to MAPKAP kinase 3 was confirmed in vitro by the precipitation of epitope-tagged CSBP1, CSBP2 and CSBP2(D168A) and endogenous CSBP from mammalian cells by a bacterially-expressed GST-MAPKAP kinase-3 fusion protein and in vivo by co-precipitation of the epitope-tagged proteins co-expressed in HeLa cells. MAPKAP kinase-3 was phosphorylated by both CSBP1 and CSBP2, and was then able to phosphorylate HSP27 in vitro. Treatment of HeLa cells with sorbitol or TNF resulted in activation of CSBP and MAPKAP kinase-3 and activation of MAPKAP kinase-3 could be blocked by preincubation of cells with 4-(4-Fluorophenyl)-2-(4-methylsulfinylphenyl)-5-4-pyridyl)-1H-imidazole, a specific inhibitor of CSBP kinase activity. These data suggest that MAPKAP kinase-3 is activated by stress and cytokines and is a novel substrate of CSBP both in vitro and in vivo. The use of MAPKAP kinase-3 in screens for the identification of pharmaceutically active compounds is disclosed.

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King of Prussia, PA, United States of America

Sanjay Kumar