The MAPK (mitogen activated protein kinase) comprises a family of ubiquitous praline-directed, protein-serine/threonine kinases which signal transduction pathways that control intracellular events including acute responses to hormones and major developmental changes in organisms (1). This super family consists of stress activated protein kinases (SAPKs); extracellular signal-regulated kinases (ERKs); and p38 kinases, each of which forms a separate pathway (2). The kinase members that populate each pathway are sequentially activated by phosphorylation. Upon activation, p38 MAPK/SAPK2α translocates into the nucleus where it phosphorylates one or more nuclear substrates, effecting transcriptional changes and other cellular processes involved in cell growth, division, differentiation, inflammation, and death (3). Specifically p38 always acts as a pro-apoptotic factor with its activation leading to the release of
cytochrome c from mitochondria and cleavage of caspase 3 and its downstream effector, PARP (4). p38 MAPK is
activated by a variety of chemical stress inducers including hydrogen peroxide, heavy metals, anisomycin, sodium salicylate, LPS, and biological stress signals such as tumor necrosis factor, interleukin-1, ionizing and UV irradiation, hyperosmotic stress and chemotherapeutic drugs (5).
As a result, p38 alpha has been widely validated as a target for inflammatory disease including rheumatoid arthritis, COPD and psoriasis (6) and has also been implicated in cancer, CNS and diabetes (7).