In human breast cancer cells, exposure to nitric oxide (NO) causes an early up-regulation of MAP kinase phosphatase 1 (MKP-1) followed by a signaling cascade that culminates in apoptosis through the mitochondria-regulated pathway. While the downstream pathway has been studied, less is known about the events occurring between NO exposure and MKP-1 up-regulation. Using microarray analysis, survivin, an antiapoptosis protein that is overexpressed in many cancers, was found to be down-regulated 4-fold and Western blot analysis confirmed that this down-regulation corresponded to the up-regulation of MKP-1. Down-regulating survivin using siRNAs facilitated MKP-1 up-regulation and rendered cells more sensitive to apoptosis by NO, while overexpressing survivin attenuated the NO-induced up-regulation of MKP-1 and made the cells more resistant to apoptosis. Chromatin immunoprecipitation identified a potential binding site for survivin approximately 1,500 base pairs upstream of the MKP-1 gene. These results demonstrate a novel inverse relationship between survivin and MKP-1 levels during NO-induced apoptosis and suggest that survivin may regulate MKP-1 by directly or indirectly (via a co-regulatory protein) binding the MKP-1 promoter.
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