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Independent mechanistic inhibition of Cdc25 phosphatases by a natural product caulibugulone

Brisson, M and Foster, C and Wipf, P and Joo, B and Tomko, RJ and Nguyen, T and Lazo, JS (2007) Independent mechanistic inhibition of Cdc25 phosphatases by a natural product caulibugulone. Molecular Pharmacology, 71 (1). 184 - 192. ISSN 0026-895X

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Abstract

Caulibugulones are novel but poorly characterized cytotoxic isoquinoline quinones and iminoquinones identified in extracts from the marine bryozoan Caulibugula intermis. We now report that the caulibugulones are selective in vitro inhibitors of the Cdc25 family of cell cycle-controlling protein phosphatases compared with either human vaccinia H1-related phosphatase (VHR) or tyrosine phosphatase 1B (PTP1B). The in vitro inhibition of Cdc25B by caulibugulone A was irreversible and attenuated by reducing agents or catalase, consistent with direct oxidation of the enzyme by reactive oxygen species. Mechanistically, caulibugulone A directly inhibited cellular Cdc25B activity, generated intracellular reactive oxygen species and arrested cells in both G 1 and G 2 /M phases of the cell cycle. Caulibugulone A also caused the selective degradation of Cdc25A protein by a process that was independent of reactive oxygen species production, proteasome activity, and the Chk1 signaling pathway. Instead, caulibugulone A stimulated the phosphorylation and subsequent activation of p38 stress kinase, leading to Cdc25A degradation. Thus, caulibugulone inhibition of cellular Cdc25A and B phosphatases occurred through at least two different mechanisms, leading to pronounced cell cycle arrest. Copyright © 2007 The American Society for Pharmacology and Experimental Therapeutics.


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Details

Item Type: Article
Status: Published
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Brisson, M
Foster, C
Wipf, Ppwipf@pitt.eduPWIPF
Joo, B
Tomko, RJ
Nguyen, T
Lazo, JS
Date: 4 January 2007
Date Type: Publication
Journal or Publication Title: Molecular Pharmacology
Volume: 71
Number: 1
Page Range: 184 - 192
DOI or Unique Handle: 10.1124/mol.106.028589
Schools and Programs: Dietrich School of Arts and Sciences > Chemistry
Refereed: Yes
ISSN: 0026-895X
MeSH Headings: Animals; Bryozoa; Cell Cycle--drug effects; Cell Cycle Proteins--antagonists & inhibitors; Cell Line; Enzyme Inhibitors--pharmacology; Etoposide--pharmacology; Humans; Isoquinolines--pharmacology; Kinetics; Nocodazole--pharmacology; Quinones--pharmacology; Tissue Extracts--pharmacology; cdc25 Phosphatases--antagonists & inhibitors
PubMed ID: 17018577
Date Deposited: 28 Oct 2013 22:25
Last Modified: 19 Mar 2019 11:55
URI: http://d-scholarship.pitt.edu/id/eprint/19894

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