tailieunhanh - Báo cáo khoa học: Nuclear localization of human spermine oxidase isoforms – possible implications in drug response and disease etiology

The recent discovery of the direct oxidation of spermine via spermine oxi-dase (SMO) as a mechanism through which specific antitumor polyamine analogues exert their cytotoxic effects has fueled interest in the study of the polyamine catabolic pathway. | ỊFEBS Journal Nuclear localization of human spermine oxidase isoforms - possible implications in drug response and disease etiology Tracy Murray-Stewart1 Yanlin Wang1 Andrew Goodwin1 Amy Hacker1 Alan Meeker2 and Robert A. Casero Jr1 1 Department of Oncology Johns Hopkins University Schoolof Medicine and the Sidney KimmelComprehensive Cancer Center at Johns Hopkins Baltimore MD USA 2 Department of Pathology Johns Hopkins University School of Medicine and the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Baltimore MD USA Keywords carcinogenesis H2O2 oxidation polyamine SMO Correspondence R. A. Casero Jr Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Bunting Blaustein Building Room 551 1650 Orleans Street Baltimore MD 21231 USA Fax 1 410 614 9884 Tel 1 410 955 8580 E-mail rcasero@ Received 7 December 2007 revised 14 March 2008 accepted 25 March 2008 doi The recent discovery of the direct oxidation of spermine via spermine oxidase SMO as a mechanism through which specific antitumor polyamine analogues exert their cytotoxic effects has fueled interest in the study of the polyamine catabolic pathway. A major byproduct of spermine oxidation is H2O2 a source of toxic reactive oxygen species. Recent targeted small interfering RNA studies have confirmed that SMO-produced reactive oxygen species are directly responsible for oxidative stress capable of inducing apoptosis and potentially mutagenic DNA damage. In the present study we describe a second catalytically active splice variant protein of the human spermine oxidase gene designated SMO5 which exhibits substrate specificities and affinities comparable to those of the originally identified human spermine oxidase-1 SMO PAOh1. and as such is an additional source of H2O2. Importantly overexpression of either of these SMO isoforms in NCI-H157 human non-small cell lung carcinoma cells resulted in significant localization of SMO protein in the nucleus as .