Rood. ions. In the mouse myonecrosis model we showed that the MAPK pathway Cidofovir (Vistide) was activated in tissues of infected mice, implying that it has an important role in the disease process. is a Gram-positive, spore-forming anaerobic rod that is present in the environment and in the gastrointestinal tract of humans and animals [1,2]. is the causative agent of both traumatic and atraumatic gas gangrene and disease is usually initiated when wounds become contaminated with either vegetative cells or spores. In atraumatic gas gangrene, infection occurs at distal sites or when there is a breach in the gastrointestinal barrier . Infection primarily occurs in severely immunocompromised hosts; is a major cause of infection in adults with severe hematological malignancies and colorectal cancer, as well as in children with severe neutropenia . The major virulence factor produced by is -toxin, a -barrel pore-forming cytolysin [5,6]. Mutagenesis studies have shown that -toxin is the primary virulence factor in mimics some of the features seen in infections is different and is poorly understood. -toxin has structural similarity to aerolysin from . It is initially secreted as inactive 46.5 kDa protoxin monomers that are capable of binding to glycosylphosphatidylinositol (GPI)-anchored proteins [8,9] in lipid rafts , via a tryptophan-rich motif located in the -toxin-mediated pore formation Rgs4 causes an influx of extracellular calcium into intoxicated C2C12 mouse myoblast cells and consequently triggers downstream signalling events. These events include activation of the calpain-cathepsin pathway, disruption of lysosomal and mitochondrial integrity, reactive-oxygen species (ROS) production and HMGB-1 nuclear translocation, all of which eventually conspire to induce cellular oncosis of the intoxicated cell . Other studies have shown that recombinant -toxin forms large diffusion pores in lipid bilayers, which Cidofovir (Vistide) in cellular systems leads to rapid potassium ion efflux, ATP depletion, necrosis and cell death . Accordingly, it is likely that the mechanism by which -toxin induces cell death is complex and most likely multifactorial. This complexity Cidofovir (Vistide) raises questions regarding the signalling events triggered within -toxin-intoxicated cells and which lead to their entry into an oncotic pathway. The mitogen activated protein kinase (MAPK) pathway is one of the major pathways activated by cells following infection and intoxication . This pathway involves the activation of a series of signals that are initiated by cellular contact with numerous stimuli and involves Cidofovir (Vistide) a series of phosphorylation events mediated by specific kinases. A MAP-kinase-kinase-kinase (MAPKKK) phosphorylates a MAP-kinase-kinase (MAPKK), which then phosphorylates a MAP-kinase (MAPK), with MAPK activation requiring both tyrosine and threonine phosphorylation [16,17,18]. The MAPK pathway is composed of three main subsets of kinases: specifically, extracellular-signal-regulated kinase (ERK) 1/2 (p42/p44), c-Jun N-terminal kinase (JNK) 1/2 (SAPK) and p38. A stimulus may specifically activate one or all of these kinase subsets and activation of one pathway may also cause the activation or deactivation of the other pathways [16,17,18]. The end result of this complex cascade is the transcriptional regulation of a broad range of physiological activities, including the release of key proinflammatory cytokines such as TNF-, as well as dictating cellular fate, migration and differentiation. Initiation of the MAPK pathway is dependent not only on the cell type, but also on the magnitude and duration of stimulation . Importantly, deregulation of MAPK signalling is implicated in a variety of diseases, including cancer. Indeed, one of the master regulators of cellular survival, Ras, is a key MAPKKK involved in ERK activation [16,20]. Ras, a GTPase that has intrinsic kinase activity, is tethered to the plasma membrane by farnesylation and activates the Raf family of protein kinases, which function as MAPKKs to eventually activate ERK [16,20]. Although MAPK activation is generally implicated in cellular survival , other studies show that this pathway plays an anti-proliferative role, particularly in regions of hypoxia and in ischemic-reperfusion injuries associated with.