title: AKT mediates actinomycin D-induced p53 expression.
abstract: At high cytotoxic concentrations, actinomycin D (ActD) blocks transcription, decreasing levels of MDM2 and thus causing p53 stabilization. At low cytostatic concentrations, ActD causes ribosomal stress, which decreases MDM2 activity, resulting in p53 stabilization and activation. ActD can thus be used for p53-based cyclotherapy. We analyzed pathways mediating ActD-induced p53 expression. Inhibitors (LY294002, wortmannin, and deguelin) of phosphatidylinositol 3-kinases (PI3K) and AKT, but not inhibitors of MEK1/2, JNK, and p38-MAPK abolished the ActD-induced p53 expression in diverse cell types. RNA interference further supported these results. When AKT was downregulated by small hairpin RNA-AKTs, ActD-induced p53 expression was significantly decreased. ActD caused AKT phosphorylation at Ser473, indicating full activation of AKT. The potential for cancer therapy is discussed.
authors: Division of Urology, Department of Surgery, Chang Gung Memorial Hospital, Chiayi, Taiwan, ROC.
authors: Chih-Shou
authors: CS
authors: Chen
authors: Dong-Ru
authors: DR
authors: Ho
authors: Fei-Yun
authors: FY
authors: Chen
authors: Chang-Rong
authors: CR
authors: Chen
authors: Yu-De
authors: YD
authors: Ke
authors: Jyan-Gwo Joseph
authors: JG
authors: Su
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D003609:Dactinomycin / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D057809:HEK293 Cells; D056945:Hep G2 Cells; D006801:Humans; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D015398:Signal Transduction; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis* / Q000378:metabolism
chemical_list: C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D003609:Dactinomycin; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt