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  • We report here that DAPK signaling pathways play significant

    2020-01-17

    We report here that DAPK signaling pathways play significant roles in OGD-induced neuronal death. Exposure of the EPZ031686 to OGD led to DAPK activation, which then promoted cell death through BimEL overexpression. Furthermore, DAPK-induced BimEL overexpression was mediated by inactivating ERK1/2 and activating JNK1/2 signal transduction pathways (Fig. 7). Thus, this study revealed new signal transduction pathways responsible for neuronal death during OGD treatment, which should assist our understanding of molecular mechanisms underlying the neuronal death during ischemic injury.
    Acknowledgements This work was supported by Kattner and Nita Graduate Scholarship and National Institutes of Health (R15NS072858). The authors declare no conflict of interest.
    Introduction Multiple myeloma (MM) is a plasma cell disorder characterized by monoclonal proteins in serum or urine, clonal plasma cells in bone marrow, and, if symptomatic, the presence of end-organ damage (CRAB criteria: hypercalcemia, renal insufficiency, anemia, bone lesions). MM accounts for approximately 10% of all hematologic malignancies and is still incurable, mainly because of its high biological heterogeneity.2, 3, 4 According to several authors, MM is consistently preceded by a monoclonal gammopathy of uncertain significance (MGUS)—an asymptomatic (no CRAB criteria) premalignant entity that has been reported to have a transformation rate to MM of approximately 1% per year. Smoldering multiple myeloma (SMM) is an intermediate asymptomatic malignant plasma cell disorder, with a risk of progression to symptomatic MM of 10% per year, for the first 5 years.1, 5, 6, 7, 8 Indeed, both MGUS and SMM represent the ideal model for studying MM precursor disease and to define and develop early intervention strategies. Aberrant CpG island methylation has been associated with various types of human malignancies, with increasing evidence suggesting that epigenetic events play a relevant role in carcinogenesis.6, 9, 10, 11, 12 The progression from MGUS to MM is the result of complex multistep genetic aberrations in addition to epigenetic modifications.8, 11, 13 The aberrant CpG island methylation of gene promoter regions of a variety of regulatory genes, associated with gene function silencing (mainly of tumor suppressor genes), has been reported in human malignancies. It was previously demonstrated that hypermethylation of the cell cycle inhibitors p15 and p16,14, 15, 16 of the apoptosis regulator death-associated protein kinase (DAPK)17, 18 and the tumor suppressor gene p53 occurs in plasma cell disorders.9, 12 However, its role in the transition from MGUS to MM has not been clarified. The p15 (INK4B) and p16 (INK4A) genes are members of the INK4 family of cyclin-dependent kinase inhibitors (CDKIs). The p15 gene is located 25 kb from the p16 gene at 9p21, and their proteins share significant areas of homologous sequences.19, 20 The p53 gene is a tumor suppressor gene that plays a critical role in cell cycle regulation, apoptosis, and cell senescence, involved in several physiologic and pathologic processes. DAP kinase, codified by the DAP kinase (DAPK) gene, localized in chromosome 9q34.1, is a calcium/calmodulin-dependent and cytoskeletal-associated serine/threonine kinase with death-inducing functions. DAPK is a positive mediator of apoptosis induced by interferon-γ, tumor necrosis factor-α, and FAS.21, 22, 23 The loss of expression of DAPK is commonly associated with hypermethylation of the DAPK gene and is frequently found in B-cell lymphoma and some carcinoma cell lines, which highlights its potential role as a tumor suppressor. Furthermore, its expression was detected in some MM cell lines and in patient-derived primary cells. The characterization of the methylation profile of candidate genes that have been established to play a role in tumorigenesis may provide significant insight into the molecular pathogenesis of MGUS and MM, in particular, the role of the aberrant methylation of the 4 described genes. Moreover, although it has been shown that methylation patterns may be related to clinical behavior, response to therapy, and survival, data are scarce regarding MGUS, SMM, and MM.24, 25