title: Cytoplasmic localization of DGKζ exerts a protective effect against p53-mediated cytotoxicity.
abstract: The transcription factor p53 plays a crucial role in coordinating the cellular response to various stresses. Therefore, p53 protein levels and activity need to be kept under tight control. We report here that diacylglycerol kinase ζ (DGKζ) binds to p53 and modulates its function both in the cytoplasm and nucleus. DGKζ, a member of the DGK family that metabolizes a lipid second messenger diacylglycerol, localizes primarily to the nucleus in various cell types. Recently, reports have described that excitotoxic stress induces DGKζ nucleocytoplasmic translocation in hippocampal neurons. In the study reported here we found that cytoplasmic DGKζ attenuates p53-mediated cytotoxicity against doxorubicin-induced DNA damage by facilitating cytoplasmic anchoring and degradation of p53 through a ubiquitin-proteasome system. Concomitantly, decreased levels of nuclear DGKζ engender downregulation of p53 transcriptional activity. Consistent with these in vitro cellular experiments, DGKζ-deficient brain exhibits high levels of p53 protein after kainate-induced seizures and even under normal conditions. These findings provide novel insights into the regulation of p53 function and suggest that DGKζ serves as a sentinel to control p53 function both during normal homeostasis and in stress responses.
authors.affiliation: Department of Anatomy and Cell Biology, Yamagata University School of Medicine, Yamagata 990-9585, Japan.
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Tanaka
authors.forename: Masashi
authors.initials: M
authors.lastname: Okada
authors.forename: Yasukazu
authors.initials: Y
authors.lastname: Hozumi
authors.forename: Ken
authors.initials: K
authors.lastname: Tachibana
authors.forename: Chifumi
authors.initials: C
authors.lastname: Kitanaka
authors.forename: Yoshioki
authors.initials: Y
authors.lastname: Hamamoto
authors.forename: Alberto M
authors.initials: AM
authors.lastname: Martelli
authors.forename: Matthew K
authors.initials: MK
authors.lastname: Topham
authors.forename: Mitsuyoshi
authors.initials: M
authors.lastname: Iino
authors.forename: Kaoru
authors.initials: K
authors.lastname: Goto
mesh_terms: D000818:Animals; D001665:Binding Sites; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D002470:Cell Survival; D003593:Cytoplasm / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D004249:DNA Damage; D019852:Diacylglycerol Kinase / Q000235:genetics / Q000378:metabolism*; D004075:Diglycerides / Q000378:metabolism*; D004317:Doxorubicin / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D007274:Injections, Intraperitoneal; D007608:Kainic Acid / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D011485:Protein Binding; D015398:Signal Transduction; D014158:Transcription, Genetic; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*; D025801:Ubiquitin / Q000235:genetics / Q000378:metabolism
chemical_list: D004075:Diglycerides; D016159:Tumor Suppressor Protein p53; D025801:Ubiquitin; D004317:Doxorubicin; D019852:Diacylglycerol Kinase; C512480:diacylglycerol kinase zeta, mouse; D046988:Proteasome Endopeptidase Complex; D007608:Kainic Acid
keywords: DGKζ; Doxorubicin; Excitotoxicity; Nucleocytoplasmic translocation; Ubiquitin–proteasome system; p53