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  • Pyrrolidinedithiocarbamate ammonium It is well established t

    2020-06-17

    It is well established that p53 maintains genomic integrity in response to a variety of cell stresses including DNA damage and oncogenic stress among others [6], [7], [8], [9]. p53 promotes the expression of several genes to cause Pyrrolidinedithiocarbamate ammonium arrest and to repair cellular damage. There is growing evidence that p53 also plays a role in modulating metabolic processes such as glycolysis, lipid synthesis and/or metabolic respiration resulting in an anti-tumorigenic effect [10], [11]. Cellular p53 levels are usually low as a result of ubiquitination and proteasomal degradation mediated by several E3 ubiquitin protein ligases [12], [13], [14], [15], [16]. The p53 tumor suppressor protein is Pyrrolidinedithiocarbamate ammonium a well-studied transcription factor that initiates a variety of cellular responses aimed at inhibiting carcinogenesis and leading to cell survival. The importance of p53 in cancer is undisputed [17], [18] and mutations in p53 contribute to many cancers [19]. Indeed, roughly half of all human cancers have mutations in the gene encoding for p53 [20] and efforts to modulate the activity of p53 are considered to be a promising form of cancer therapy [21], [22], [23], [24].
    Experimental
    Results
    Discussion We find that DGKε−/− MEFs exhibit a higher level of GK than the WT counterparts (Fig. 3). The transcription factor p53 increases the expression of GK [3], [5]. The present study suggests that DGKε plays a role as a negative regulator of p53 levels in fibroblasts. This is indicated by our finding that DGKε−/− MEFs have higher levels of p53 than WT MEFs (Fig. 5). The effect of DGKε on p53 provides a potential explanation for our earlier observation that knocking out DGKε results in an increased incorporation of glycerol into lipids [1]. This increased incorporation of glycerol into lipids occurs despite the fact that DGKε affects only the nature of lipid acyl chains and has little effect on the rate of synthesis of lipids [35]. The phosphorylation of glycerol by GK entraps this metabolite within the cell [2], resulting in greater incorporation of the metabolite into lipid. Both the expression of GK (Fig. 3) as well as the activity of GK (Fig. 4) is greater in DGKε−/− MEFs than in WT MEFs. The importance of GK in promoting the synthesis of lipids is shown by the observation that this phenomenon does not occur in DGKε−/− MEFs when either acetate or pyruvate is used as a precursor (Fig. 2). We provide further evidence that the changes in GK and p53 expression in the DGKε−/− MEFs is a consequence of lower DGKε. Transfecting DGKε−/− MEFs with FLAG-DGKε plasmids resulted in expression of sufficient amounts of the coded protein to be detectable with Western blots (Fig. 5). As a result of the increased DGKε expression there was a significantly lower (p<0.05) expression of p53 (Fig. 5) and a trend towards lower levels of GK (Fig. 3) in the transfected cells when compared with the DGKε−/− MEFs. Our findings present the possibility that inhibition of DGKε could be a target for cancer therapy. This strategy could be particularly effective for brain 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.