Our findings present the possibility that

Our findings present the possibility that inhibition of DGKε could be a target for cancer therapy. This strategy could be particularly effective for Fmoc-Gln(Trt)-OH australia tumors, since the brain has a high expression of DGKε. There is a human disease that has been shown to be associated with a mutation of the DGKE gene. Loss-of-function mutations in DGKε cause atypical hemolytic-uremic syndrome [36]. It has also been found using endothelial cells that have been knocked down for DGKε with siRNA, resulted in an increased activation of several phosphoproteins, with p38-MAPK showing the greatest activation [37]. This work also showed that siRNA knockdown of DGKε resulted in increased apoptosis and inhibition of cell migration and angiogenesis, suggesting that DGKε inhibition is a potential anti-cancer strategy. It was suggested that the knockdown of DGKε expression could result in higher levels of DG that would activate protein kinase C, an enzyme that catalyzes the phosphorylation of p38-MAPK. The p38-MAPK in turn has been shown to phosphorylate and activate p53 [38], providing a plausible mechanism for the relationship between DGKε and p53. DGKε is not the only DGK isoform that has been associated with p53. It has been shown that DGKζ binds to p53 and modulates its activity in both the cytoplasm and the nucleus [39]. In the cytosol DGKζ promotes the degradation of p53 through the ubiquitin-proteosome system [39], also a likely mechanism to explain the low levels of p53 in the DGKε-WT cells. It is also reported that DGKζ-deficient brain exhibits a high level of p53 protein [39], analogous to what we have shown with the DGKε−/− MEFs (Fig. 5). In addition, DGKζ can translocate to the nucleus. Inhibition of DGKζ expression in the nucleus results in the specific downregulation of the transcriptional activity of p53 [39]. Another DGK isoform, DGKα is activated by p53 [40]. Thus, loss of DGKε or DGKζ would result in an increase in p53, which in turn would cause the activation of DGKα. Higher activity of DGKα results in better survival rates of lung cancer patients [41]. Thus, we conclude that the observed increased expression and activity of GK in DGKε−/− MEFs provides a mechanism to explain the increased incorporation of glycerol into lipid that we had found in these cells. The increased GK levels in these cells can be explained by the increase in p53, a known transcription factor for the expression of this enzyme. A scheme describing these relationships is shown in Fig. 7. p53 is closely associated with cell survival and has an important role in cancer. Further studies are needed to fully understand how various isoforms of diacylglycerol kinase affect p53 signaling.
Conflict of interest
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Acknowledgements We thank Dr. Fred Y. Xu for technical support. Supported by grants from the Natural Sciences and Engineering Research Council of Canada (Grant 9848, to RME) and from the Heart and Stroke Foundation of Canada (Grant G-14-0005708 to G.M.H.). G.M.H. is a Canada Research Chair in Molecular Cardiolipin Metabolism.