The role of the p53 protein in nitrosative stress-induced apoptosis of PC12 rat pheochromocytoma cells.

Autor: Varga J; Department of Medical Biology, Medical School, University of Pécs, Szigeti út 12, H-7624, Pécs, Hungary., Bátor J, Péter M, Árvai Z, Pap M, Sétáló G Jr, Szeberényi J
Jazyk: angličtina
Zdroj: Cell and tissue research [Cell Tissue Res] 2014 Oct; Vol. 358 (1), pp. 65-74. Date of Electronic Publication: 2014 Jun 25.
DOI: 10.1007/s00441-014-1932-7
Abstrakt: PC12 rat pheochromocytoma cells are widely used to investigate signaling pathways. The p143p53PC12 cell line expresses a Val143Ala mutant p53 protein that is less capable of binding to the p53 consensus site in DNA than its wild-type counterpart. Nitric oxide (NO), depending on its concentration, is able to activate several signal transduction pathways. We used sodium nitroprusside (SNP), an NO donor compound, to analyze NO-induced cellular stress in order to clarify the mechanism and role of nitrosative stress in pathological processes, including inflammation and cancer. SNP caused cell death when applied at a concentration of 400 μM, p143p53PC12 cells showing higher sensitivity than wild-type PC12 cells. The mechanisms leading to the increased SNP-sensitivity of p143p53PC12 cells were then investigated. The 400-μM SNP treatment caused stress kinase activation, phosphorylation of the eukaryotic initiation factor eIF2α and p53 protein, proteolytic activation of protein kinase R, caspase-9, and caspase-3, p53 stabilization, CHOP induction, cytochrome c release from mitochondria, and a decline in the level of the Bcl-2 protein in both cell lines. All these SNP-induced changes were more robust and/or permanent in cells with the mutant p53 protein. We thus conclude that (1) the main cause of the SNP-induced apoptosis of PC12 cells is the repression of the bcl-2 gene, evoked through p53 stabilization, stress kinase activation, and CHOP induction; (2) the higher SNP sensitivity of p143p53PC12 cells is the consequence of the stronger and earlier activation of the intrinsic apoptotic pathway.
Databáze: MEDLINE
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