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Redox regulation of Cdc25B by cell-active quinolinediones

Brisson, M and Nguyen, T and Wipf, P and Joo, B and Day, BW and Skoko, JS and Schreiber, EM and Foster, C and Bansal, P and Lazo, JS (2005) Redox regulation of Cdc25B by cell-active quinolinediones. Molecular Pharmacology, 68 (6). 1810 - 1820. ISSN 0026-895X

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Abstract

Intracellular reduction and oxidation pathways regulate protein functionality through both reversible and irreversible mechanisms. The Cdc25 phosphatases, which control cell cycle progression, are potential subjects of oxidative regulation. Many of the more potent Cdc25 phosphatase inhibitors reported to date are quinones, which are capable of redox cycling. Therefore, we used the previously characterized quinolinedione Cdc25 inhibitor DA3003-1 [NSC 663284 or 6-chloro-7-(2-morpholin-4-yl-ethylamino)-quinoline-5,8-dione] and a newly synthesized congener JUN1111 [7-(2-morpholin-4-yl-ethylamino)-quinoline-5, 8-dione] to test the hypothesis that quinone inhibitors of Cdc25 regulate phosphatase activity through redox mechanisms. Like DA3003-1, JUN1111 selectively inhibited Cdc25 phosphatases in vitro in an irreversible, time-dependent manner and arrested cells in the G 1 and G 2 /M phases of the cell cycle. It is noteworthy that both DA3003-1 and JUN1111 directly inhibited Cdc25B activity in cells. Depletion of glutathione increased cellular sensitivity to DA3003-1 and JUN1111, and in vitro Cdc25B inhibition by these compounds was sensitive to pH, catalase, and reductants (dithiothreitol and glutathione), consistent with oxidative inactivation. In addition, both DA3003-1 and JUN1111 rapidly generated intracellular reactive oxygen species. Analysis of Cdc25B by mass spectrometry revealed sulfonic acid formation on the catalytic cysteine of Cdc25B after in vitro treatment with DA3003-1. These results indicate that irreversible oxidation of the catalytic cysteine of Cdc25B is indeed a mechanism by which these quinolinediones inactivate this protein phosphatase. Copyright © 2005 The American Society for Pharmacology and Experimental Therapeutics.


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Details

Item Type: Article
Status: Published
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Brisson, M
Nguyen, T
Wipf, Ppwipf@pitt.eduPWIPF
Joo, B
Day, BW
Skoko, JS
Schreiber, EM
Foster, C
Bansal, P
Lazo, JS
Date: 1 December 2005
Date Type: Publication
Journal or Publication Title: Molecular Pharmacology
Volume: 68
Number: 6
Page Range: 1810 - 1820
DOI or Unique Handle: 10.1124/mol.105.016360
Schools and Programs: Dietrich School of Arts and Sciences > Chemistry
Refereed: Yes
ISSN: 0026-895X
MeSH Headings: Cell Cycle Proteins--antagonists & inhibitors; Cell Cycle Proteins--metabolism; Glutathione--metabolism; HeLa Cells; Humans; Interphase; Mass Spectrometry; Oxidation-Reduction; Quinolines--pharmacology; Reactive Oxygen Species--metabolism; Sulfonic Acids--metabolism; Transfection; cdc25 Phosphatases--antagonists & inhibitors; cdc25 Phosphatases--metabolism
PubMed ID: 16155209
Date Deposited: 31 Oct 2013 18:13
Last Modified: 19 Mar 2019 11:55
URI: http://d-scholarship.pitt.edu/id/eprint/19944

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