NF-κB is involved in the activation of microglia, which induces secondary spinal cord injury (SCI). This process involves the activation of NF-κB signaling pathway by TRAF6 through its polyubiquitination function. We know that deubiquitination of TRAF6 mediated by deubiquitinating enzyme (DUB) significantly inhibits activation of NF-κB pathway. The ubiquitin-specific protease 4 (USP4) belongs to the deubiquitinase family. Therefore, we hypothesize that USP4 is involved in the microglial activation and subsequent neuronal inflammation after SCI. In this study, we examined the expression and the role of USP4 after SCI. Western blot analysis showed that the expression of USP4 was downregulated and the expression of p-p65 was upregulated in the spinal cord after SCI. Immunohistochemical and immunofluorescence staining showed that USP4 was expressed in microglia but its expression decreased after SCI. In vitro LPS-induced activation of microglia showed decreased expression of USP4 and increased expression of p-p65 and TRAF6. USP4 silencing in LPS-induced activation of microglia promoted the expression of p-p65 and TRAF6 and the secretion of TNF-α and IL-1β. In conclusion, our study provides the first evidence that in microglial cells expression of USP4 decreases after SCI in rats. The downregulation of USP4 expression may promote microglial activation and subsequent neuronal inflammation through NF-κB by attenuating the deubiquitination of TRAF6. This mechanism is of great significance in the pathophysiology of secondary SCI.
Eph receptor A4 (EphA4), a member of the erythropoietin-producing hepatocellular (Eph) family, has been reported to upregulate in several tumors. However, the role of EphA4 in multiple myeloma has not been clarified yet. In this study, we found that EphA4 promoted proliferation of multiple myeloma cells via the regulation of cell cycle. Besides, EphA4 was closely related to cell adhesion of multiple myeloma cells and promoted cell adhesion–mediated drug resistance by enhancing the phosphorylation levels of Akt (p-AKT) expression in multiple myeloma. More interestingly, we discovered that EphA4 can interact with cyclin-dependent kinase 5 (CDK5) and regulate its expression in multiple myeloma. CDK5 has been reported to be overexpressed in multiple myeloma which mediated bortezomib resistance and also participated in AKT pathway. And we have also proved the fact. So, we supposed that EphA4 interacted with CDK5 and promoted its expression which in turn enhanced p-AKT expression and promoted cell adhesion–mediated drug resistance in multiple myeloma. Therefore, this study clarifies the molecular mechanism of cell adhesion–mediated drug resistance and may be useful in identifying potential target for treatment of multiple myeloma.
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