Inactivation of wild-type p53 protein function by reactive oxygen and nitrogen species in malignant glioma cells.
Malignant gliomas are the most common primary brain tumors in adults, and the most malignant form, glioblastoma multiforme (GBM), is usually rapidly fatal. Most GBMs do not have p53 mutations, although the p53 tumor suppressor pathway appears to be inactivated. GBMs grow in a hypoxic and inflammatory microenvironment, and increased levels of the free radicals nitric oxide (NO) and superoxide () occur in these malignancies in vivo. Peroxynitrite (ONOO(-)) is a highly reactive molecule produced by excess NO and that can posttranslationally modify and inactivate proteins, especially zinc finger transcription factors such as p53. We demonstrated previously that GBMs have evidence of tyrosine nitration, the "footprint" of peroxynitrite-mediated protein modification in vivo, and that peroxynitrite could inhibit the specific DNA binding ability of wild-type p53 protein in glioma cells in vitro. Here we show that both authentic peroxynitrite and SIN-1 (3-morpholinosydnonimine hydrochloride), a molecule that decomposes into NO and to form peroxynitrite, can inhibit wild-type p53 function in malignant glioma cells. Concentrations of peroxynitrite associated with a tumor inflammatory environment caused dysregulation of wild-type p53 transcriptional activity and downstream p21(WAF1) expression.
Cobbs
Charles S
CS
Surgical Service, Veterans Affairs Medical Center, University of Alabama at Birmingham Department of Surgery, Division of Neurosurgery, Birmingham, Alabama 35294, USA. cscobbs@uabmc.edu
Whisenhunt
Thomas R
TR
Wesemann
Duane R
DR
Harkins
Lualhati E
LE
Van Meir
Erwin G
EG
Samanta
Minu
M
D045744:Cell Line, Tumor; D004318:Doxycycline / Q000494:pharmacology; D005909:Glioblastoma / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008981:Molsidomine / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology; D030421:Peroxynitrous Acid / Q000493:pharmacokinetics / Q000494:pharmacology*; D026361:Reactive Nitrogen Species / Q000493:pharmacokinetics / Q000494:pharmacology*; D017382:Reactive Oxygen Species / Q000493:pharmacokinetics / Q000494:pharmacology*; D015533:Transcriptional Activation / Q000187:drug effects; D014162:Transfection; D016159:Tumor Suppressor Protein p53 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000502:physiology
D026361:Reactive Nitrogen Species; D017382:Reactive Oxygen Species; D016159:Tumor Suppressor Protein p53; D030421:Peroxynitrous Acid; C002385:linsidomine; D008981:Molsidomine; D004318:Doxycycline