The natural toxin juglone causes degradation of p53 and induces rapid H2AX phosphorylation and cell death in human fibroblasts.
Juglone (5-hydroxy-1,4-naphtoquinone) is a natural toxin produced by walnut trees. In this study we show that juglone differentially reduces viability of human cells in culture. Normal fibroblast were found to be especially sensitive to juglone and lost viability primarily through a rapid apoptotic and necrotic response. This response may have been triggered by DNA damage since juglone induced a rapid and strong phosphorylation of H2AX in all phases of the cell cycle. Furthermore, juglone inhibits mRNA synthesis in human fibroblasts in a dose-dependent manner. Surprisingly, juglone caused a drastic reduction of the basal level of p53 in human fibroblasts and this loss could not be fully rescued by proteasome and calpain I inhibitors. However, when cells were pretreated with UV light or ionizing radiation, juglone was not able to reduce the cellular levels of activated p53. Our results show that juglone has multiple effects on cells such as the induction of DNA damage, inhibition of transcription, reduction of p53 protein levels and the induction of cell death.
Paulsen
Michelle T
MT
Division of Radiation and Cancer Biology, Department of Radiation Oncology, University of Michigan Medical School, Ann Arbor, MI 48109-0936, USA.
Ljungman
Mats
M
D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D002154:Calpain / Q000037:antagonists & inhibitors / Q000502:physiology; D016923:Cell Death / Q000187:drug effects / Q000528:radiation effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D003603:Cytotoxins / Q000633:toxicity*; D005347:Fibroblasts / Q000187:drug effects* / Q000378:metabolism* / Q000528:radiation effects; D005434:Flow Cytometry; D006657:Histones / Q000378:metabolism*; D006801:Humans; D009285:Naphthoquinones / Q000633:toxicity*; D009336:Necrosis; D010766:Phosphorylation / Q000187:drug effects; D046988:Proteasome Endopeptidase Complex / Q000494:pharmacology; D012333:RNA, Messenger / Q000096:biosynthesis; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D014466:Ultraviolet Rays
D015853:Cysteine Proteinase Inhibitors; D003603:Cytotoxins; C468783:H2AX protein, human; D006657:Histones; D009285:Naphthoquinones; D012333:RNA, Messenger; D016159:Tumor Suppressor Protein p53; D002154:Calpain; D046988:Proteasome Endopeptidase Complex; C005134:juglone