Modulation of p53 by mitogen-activated protein kinase pathways and protein kinase C δ during avian reovirus S1133-induced apoptosis

Abstract

ARV S1133 infection caused apoptosis in vivo and in vitro; however, the intracellular signaling pathways have not been fully delineated. We have previously demonstrated that ARV S1133 activates proapoptotic signaling from Src to p53, and further investigated how ARV S1133 modulates p53. We found that ARV S1133 forms syncytia and induces apoptosis in CEF, DF1 and Vero cells with different kinetics. Enhancement of p53 phosphorylation and DNA-binding capacity to bax and bad promoters was found in this study to increase bax and bad expression in ARV S1133-infected cells. ARV S1133 activates PKC delta and p38 and JNK/SAPK pathways, and inhibition of Ras, p38, JNK/SAPK and PKC delta works efficiently against apoptosis. Suppression of p38, JNK/SAPK and PKC delta selectively abolished ARV S1133-mediated p53 phosphorylation; moreover, inhibition of Src did not affect ARV S1133-induced p38 and JNK/SAPK activation, whereas blocking of Ras resulted in a reduction in the activities of p38 and JNK/SAPK.

Cell Entry of Avian Reovirus Follows a Caveolin-1-mediated and Dynamin-2-dependent Endocytic Pathway That Requires Activation of p38 Mitogen-activated Protein Kinase (MAPK) and Src Signaling Pathways as Well as Microtubules and Small GTPase Rab5 Protein

“…6C, p-p38 MAPK was not suppressed by PP2 inhibitor or overexpression of Csk, suggesting that Src is not the upstream inducer of p38 MAPK. These data are in agreement with our earlier report (33). It is also interesting to note that the expression level of p38 MAPK and Src in caveolin-1 or dynamin-2 siRNA-treated cell lysates was not significantly altered (Fig.…”

“…It was an extension of earlier studies by our laboratory in which it was discovered that p38 MAPK and Src signaling pathways triggered by ARV that are beneficial for ARV replication and apoptosis induction (31,33). In this study, the use of a panel of chemical inhibitors, DN mutants together with siRNAs targeting caveolin-1 and dynamin-2 to characterize ARV entry into host cells revealed that ARV uses a cholesterol and caveolin-1-mediated and dynamin-2-dependent endocytosis that requires activation of Ras, p38 MAPK, and Src signaling pathways.…”

“…ARV Activates Src and p38 MAPK During the Very Early Stage of Life Cycle-More recently, we have demonstrated that activation of p38 MAPK and Src has been shown to up-regulate p53 upon ARV infection that is required for induction of apoptosis (33). In this study, we found that a significant increase in the phosphorylation level of Src and p38 MAPK in ARV-infected Vero and DF-1 cells was seen as early as 5 min postinfection, attaining a maximal level at 10 or 15 min post-infection, respectively (Fig.…”

“…For the past several years, our laboratory has been studying molecular evolution of ARV and signaling pathways triggered by ARV required for apoptosis induction, virus replication, and cell cycle perturbations (22,(27)(28)(29)(30)(31)(32)(33). To date, the molecular events leading to endocytosis by ARV are still completely unknown.…”

Strong Concordance Between Transcriptomic Patterns of Spleen and Peripheral Blood Leukocytes in Response to Avian Pathogenic Escherichia coli Infection

“…Enrichment of the MAPK pathway within the PBLs at 1 DPI is hypothesized to cause the downstream changes in cytokine-cytokine receptor and p53 signaling seen in the spleen at 5 DPI. MAPK and p53 pathways are associated with apoptosis, tumor suppression, and viral infection (15,29). The increase in apoptotic activity in the birds with severe pathology may contribute to the observed pathology.…”