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p38 MAPK Signaling in Oral-related Diseases

¹ Department of Oral Biology, State University of New York at Buffalo, 3435 Main Street, Buffalo, NY 14214-3008, USA; and
² Department of Periodontics and Oral Medicine, University of Michigan, 1011 N. University Avenue, Ann Arbor, MI 48109-1078, USA

View larger version (25K): [in this window] [in a new window]   Figure 1. Schematic representation of dental diseases where p38 MAPK signaling has been shown to play a significant role relative to the pathobiology of the disease.

View larger version (43K): [in this window] [in a new window]   Figure 2. A. actinomycetemcomitans LPS induces significant linear bone loss, which is blocked by an orally active p38 inhibitor. (A) Reformatted µCT isoform display from 8-week-old A. actinomycetemcomitans LPS-injected rat maxillae exhibits dramatic palatal and interproximal bone loss. Landmarks used for linear measurements were the cemento-enamel junction (CEJ) to the alveolar bone crest (ABC). (B) Linear bone loss as measured from the CEJ to the ABC (mean ± SEM). Significant bone loss (p < 0.01) was observed between control (n = 6) and A. actinomycetemcomitans LPS-injected rats (n = 12). Significant reduction of LPS-induced periodontal bone loss (**p < 0.01 for SD-282 [15 mg/kg; n = 8] and *p < 0.05 for SD-282 [45 mg/kg; n = 8]). Used with permission (Kirkwood et al., 2007).

View larger version (34K): [in this window] [in a new window]   Figure 3. RNA-binding proteins mediate regulation of cytokine mRNA stability through p38/MK2 signaling. LPS activates p38 MAPK signaling in a variety of cells, leading to transcriptional activation of cytokine genes or enhanced mRNA stability and translation (highlighted areas). The fate of ARE mRNA is dependent on the presence of destabilizing and stabilizing mRNA binding proteins. p38 MAPK activates MK2 in the nucleus, allowing for MK2 translocation to the cytoplasm. MK2 subsequently phosphorylates destabilizing mRNA-binding proteins such as TTP. This action prevents TTP from interacting with ARE cytokines. Simultaneously, activation of the p38 MAPK pathway results in translocation of HuR, a stabilizing RNA-binding protein, from the nucleus to the cytoplasm. Thus, upon p38/MK2 activation and phosphorylation of TTP, cytokine mRNA stability is enhanced, because TTP is no longer dictating mRNA triage and exonuclease decay.

View larger version (30K): [in this window] [in a new window]   Figure 4. Molecular actions of TTP to ensure that rapid mRNA decay is mediated through p38 MAPK signaling. In the absence of inflammatory stimulation, TTP binds ARE cytokine mRNA and shuttles the message to exosomal and P-body degradation sites, where mRNA is degraded by exonucleases in the 3' to 5' direction or the 5' to 3' direction, respectively. Upon activation of the p38 MAPK-MK2 pathway, TTP is phosphorylated at serines 52 and 178. Phosphorylation at these sites sequesters TTP from ARE mRNA and allows for interaction with 14-3-3 proteins. The ARE mRNAs are now capable of interacting with stabilizing components, which shuttle the transcript to translational machinery (see text for details).