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381 AN INVERSE INTERACTION BETWEEN SURVIVIN AND MAP KINASE PHOSPHATASE 1 REGULATES NITRIC OXIDE-INDUCED APOPTOSIS.
  1. J. C. Wen,
  2. G. Chaudhuri,
  3. S. Pervin
  1. Department of Obstetrics and Gynecology, David Geffen School of Medicine at University of California, Los Angeles, CA

Abstract

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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