RRC ID 68710
著者 Tanaka T, Okada M, Hozumi Y, Tachibana K, Kitanaka C, Hamamoto Y, Martelli AM, Topham MK, Iino M, Goto K.
タイトル Cytoplasmic localization of DGKζ exerts a protective effect against p53-mediated cytotoxicity.
ジャーナル J Cell Sci
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.
巻・号 126(Pt 13)
ページ 2785-97
公開日 2013-7-1
DOI 10.1242/jcs.118711
PII jcs.118711
PMID 23606744
MeSH Animals Binding Sites Cell Line, Tumor Cell Nucleus / drug effects Cell Nucleus / genetics Cell Nucleus / metabolism Cell Survival Cytoplasm / drug effects Cytoplasm / genetics Cytoplasm / metabolism* DNA Damage Diacylglycerol Kinase / genetics Diacylglycerol Kinase / metabolism* Diglycerides / metabolism* Doxorubicin / pharmacology Gene Expression Regulation / drug effects Humans Injections, Intraperitoneal Kainic Acid / pharmacology Male Mice Mice, Inbred C57BL Proteasome Endopeptidase Complex / metabolism Protein Binding Signal Transduction Transcription, Genetic Tumor Suppressor Protein p53 / genetics Tumor Suppressor Protein p53 / metabolism* Ubiquitin / genetics Ubiquitin / metabolism
IF 4.573
リソース情報
ヒト・動物細胞 HeLa(RCB0007) 293(RCB1637)