Sentinel role for DGKζ regulation of p53

In response to stress, the p53 tumour suppressor protein coordinates a number of cellular responses and, as such, requires tight regulation. Diacylglycerol kinase ζ (DGKζ) is a member of the DGK family that metabolises the lipid second messenger diacylglycerol, and contains a nuclear localisation signal (NLS). Kaoru Goto and colleagues have previously predicted that DGKζ is involved in stress responses, and indeed, they have reported that excitotoxic stress induces nucleocytoplasmic translocation of DGKζ in hippocampal neurons, but just how this kinase is involved in stress responses is unclear. Now (p. 2785), the authors examine a pathophysiological link between the cytoplasmic translocation of DGKζ and p53-mediated cytotoxicity following doxorubicin-induced DNA damage. In vitro experiments showed that overexpressing wild-type DGKζ (which is predominant in the nucleus) suppressed p53 induction and reduced apoptosis, but these effects were even more pronounced when overexpressing an NLS-deleted mutant DGKζΔNLS, which is predominant in the cytoplasm. Furthermore, the authors show that cytoplasmic DGKζΔNLS induces cytoplasmic localisation of p53 and enhances its degradation through the ubiquitin–proteasome system. Next, the authors provide in vivo evidence that p53 protein levels are upregulated in DGKζ-deficient mouse brain under both stressed (excitotoxin-induced seizures) and nonstressed conditions. These results suggest that DGKζ is a novel regulatory factor important for p53 function.