DGKζ ablation engenders upregulation of p53 level in the spleen upon whole-body ionizing radiation

Adv Biol Regul. 2018 Jan;67:93-100. doi: 10.1016/j.jbior.2017.09.010. Epub 2017 Sep 28.

Abstract

The tumor suppressor gene product p53, which coordinates the cellular response to various stresses, is subject to tight regulation by a complex network of signal transduction. The DGK family metabolizes lipidic second messenger diacylglycerol to produce phosphatidic acid. Our earlier studies showed that one isozyme, DGKζ, is involved in the regulatory mechanism of p53. In a cellular model of doxorubicin-induced DNA damage, overexpression of wild-type DGKζ suppresses p53 protein induction and reduces apoptosis, whereas knockdown of DGKζ upregulates p53 protein level and promotes apoptosis. Further examination reveals that DGKζ facilitates p53 degradation via ubiquitin-proteasome system in the cytoplasm. However, it remains undetermined whether the regulatory mechanism of DGKζ on p53 function found in cell-based experiments is also functional at the animal level. This study was conducted to elucidate this point using an experiment with DGKζ-KO mice under DNA damage induced by whole-body ionizing radiation. Our results reveal that p53 protein is induced robustly in the spleen of DGKζ-KO mice upon exposure to ionizing radiation, thereby promoting apoptosis in this organ. Taken together, the results demonstrate that DGKζ plays a sentinel role in p53 expression at the cellular and organismal levels after DNA damaging stress conditions.

Keywords: Apoptosis; Diacylglycerol kinase ζ; Ionizing radiation; Mdm2; Spleen; p53.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cytoplasm / genetics
  • Cytoplasm / metabolism
  • DNA Damage*
  • Diacylglycerol Kinase / genetics
  • Diacylglycerol Kinase / metabolism*
  • Mice
  • Mice, Knockout
  • Proteolysis / radiation effects*
  • Rats
  • Tumor Suppressor Protein p53 / biosynthesis*
  • Tumor Suppressor Protein p53 / genetics
  • Up-Regulation / radiation effects*
  • Whole-Body Irradiation*
  • X-Rays / adverse effects*

Substances

  • Trp53 protein, mouse
  • Tumor Suppressor Protein p53
  • Diacylglycerol Kinase
  • diacylglycerol kinase zeta, mouse