Functional role of p38 MAPK Sample Clauses

Functional role of p38 MAPK. Activation of p38 was first revealed to be a common event triggered by pro- inflammatory cytokine receptor activation and one that is essential for inflammation. Evidence also links p38 signaling to the control of cell homeostasis through modulation of transcription factors, cytoskeleton elements and other kinases. It is still controversial whether activation of p38 primarily leads to continued cell survival or cell death. However, data implies the p38 can function in both capacities, depending on the stimuli and ultimately the targets of p38 MAPK signaling. Subcellular localization of p38 may also impact the function of p38 (77). The outcome of p38 activation, however, is most likely dependent on how the balance between apoptosis and survival is shifted and which side is dominant. Mediator of inflammation Around the time when p38 was first cloned, it was also discovered to be the target of cytokine-suppressive anti-inflammatory drugs (CSAIDs) and often referred to as CSAID binding proteins (CSBPs) (78). CSAIDs exert their anti-inflammatory activity by inhibiting cytokine biosynthesis and were found to be potent and selective inhibitors of the p38 MAPK pathway. This finding connected p38 MAPK to cytokine production and the inflammatory response (79). Since then, p38 MAPK is thought to participate in the expression of pro-inflammatory mediators like the cytokine interleukin-6 (IL-6) and the inducible XXX-2 via the NF-κB-mediated transcription. Chemical stresses that are known to induce XXX-2 expression do so through a p38-dependent mechanism (80). Published reports suggest that p38 potentially acts at various points in the NF-κB pathway since pharmacological inhibition of p38 MAPK has been shown to attenuate NF-κB transactivation without affecting NF-κB DNA binding (81, 82). p38 is known to phosphorylate the p65 subunit of NF-κB in the transactivation domain and possibly up- regulate transcription in this manner (83, 84). Another mechanism that has been proposed suggests that p38 phosphorylates transcriptional co-activations like CREB needed for NF-κB-mediated transcription (85). p38 has also plays a role in the mRNA stability of cytokines. Cytokine mRNAs typically have a short half-life due to the 3’ untranslated region (UTR) AU rich elements where AU rich element binding proteins (ARE-BPs) bind and target the mRNA for degradation. In basal control conditions of p38 MAPK, transcript stability is low but increase with the activation of the p38 pathway. This...