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Papers In Press, published online ahead of print November 28, 2005
Dep. of Life Science, POSTECH, Pohang, Kyoungbook 790-784
Corresponding Author: ktk{at}postech.ac.kr
Selective cell death of dopaminergic neurons in the substantia nigra (SN) is the major cause of Parkinson’s disease. Current evidence suggests that this cell death could be mediated by nitric oxide byproducts such as nitrate and peroxynitrite. Since protein kinase C (PKC)-d is implicated in apoptosis of various cell types, we studied its roles and activation mechanisms in Nitric Oxide (NO)-induced apoptosis of SN4741 dopaminergic cells. When cells were treated with sodium nitroprusside (SNP), a NO donor, endogenous PKC-d was nitrated and activated. Immunoprecipitation revealed that p53 co-immunoprecipitated with PKC-d and was phosphorylated at the 15th serine residue in SNP-treated cells. An in vitro kinase assay revealed that p53 was directly phosphorylated by SNP-activated PKC-d. The p53 ser15 phosphorylation was suppressed in SNP-treated cells when the NO-mediated activation of PKC-d was inhibited by rottlerin or (-)-epigallocatechin gallate (EGCG). Within 3 hours of p53 phosphorylation, its protein levels increased due to decreased ubiquitin-dependent proteosomal proteolysis, while the protein levels of mdm2, E3 ubiquitin ligase, was down-regulated in a p53 phosphorylation-dependent fashion. Taken together, these results demonstrate that nitration-mediated activation of PKC-d induces the phosphorylation of the ser15 residue in p53, which increases its protein stability, thereby contributing to the nitric oxide-mediated apoptosis-like cell death pathway. These findings may be expanded to provide new insight into the cellular mechanisms of Parkinson’s Disease.
J. Biol. Chem, 10.1074/jbc.M509509200
Submitted on August 29, 2005
Accepted on November 28, 2005
Regulation of p53 by activated protein kinase C
during nitric oxide induced dopaminergic cell death
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