Evidence for peroxynitrite-mediated modifications to p53 in human gliomas: possible functional consequences
C S Cobbs1, M Samanta, L E Harkins
1Department of Surgery, Birmingham Veterans Affairs Hospital, Birmingham, Alabama 35294, USA.
Archives of Biochemistry and Biophysics
|October 12, 2001
Summary
Peroxynitrite, a reactive molecule, is found in human gliomas and modifies the tumor suppressor protein p53. This modification leads to impaired p53 DNA binding, potentially contributing to glioma development.
Area of Science:
- Neuro-oncology
- Biochemistry
- Molecular Biology
Background:
- Increased nitric oxide synthase (NOS) expression is observed in human gliomas.
- Nitric oxide (NO) and superoxide (O(*-)(2)) can form peroxynitrite, a reactive metabolite.
- The role of peroxynitrite in glioma pathogenesis is not well understood.
Purpose of the Study:
- To investigate the presence and impact of peroxynitrite in human gliomas.
- To determine if peroxynitrite modifies key proteins like p53 in gliomas.
- To elucidate the functional consequences of peroxynitrite-mediated p53 modification.
Main Methods:
- Detection of nitrotyrosine, a marker of peroxynitrite, in human glioma tissues.
- In vitro experiments treating recombinant wild-type p53 and glioma cell lysates with peroxynitrite.
- Assessing p53 aggregation, tyrosine nitration, and DNA binding ability after peroxynitrite treatment.
Main Results:
- Nitrotyrosine is present in human malignant gliomas, indicating in vivo peroxynitrite formation.
- p53, a tumor suppressor, shows evidence of peroxynitrite-mediated modifications in gliomas.
- Peroxynitrite treatment in vitro causes p53 aggregation, nitration, and loss of DNA binding.
Conclusions:
- Tyrosine nitration of proteins, including p53, occurs in human gliomas.
- p53 is a potential target of peroxynitrite in gliomas.
- Peroxynitrite can impair wild-type p53 function through posttranslational modifications, suggesting a role in glioma development.
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