This Article Full Text Full Text (PDF) Supplementary Data Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Tomko, R. J. Articles by Lazo, J. S. Search for Related Content PubMed PubMed Citation Articles by Tomko, R. J., Jr. Articles by Lazo, J. S.

Multimodal Control of Cdc25A by Nitrosative Stress

Department of Pharmacology and Chemical Biology and University of Pittsburgh Drug Discovery Institute, University of Pittsburgh, Pittsburgh, Pennsylvania

Requests for reprints: John S. Lazo, University of Pittsburgh Drug Discovery Institute, Biomedical Science Tower 3, Suite 10040, 3501 Fifth Avenue, University of Pittsburgh, Pittsburgh, PA 15260. Phone: 412-648-9200; Fax: 412-648-9009; E-mail: lazo{at}pitt.edu.

Key Words: Cdc25A • nitric oxide • redox • eIF2 • apoptosis signal-regulating kinase 1

Cdc25A propels cell cycle progression, is overexpressed in numerous human cancers, and possesses oncogenic and antiapoptotic activities. Reactive oxygen species, such as hydrogen peroxide, regulate Cdc25A, but the physiologic and pathologic effects of nitric oxide (NO) and NO-derived reactive species are not well defined. Herein, we report novel independent mechanisms governing Cdc25A in response to nitrosative insult. We observed direct and rapid inhibition of Cdc25A phosphatase activity after in vitro treatment with the low molecular mass cell-permeable S-nitrosothiol S-nitrosocysteine ethyl ester (SNCEE). In addition, treatment of cancer cells with SNCEE induced nitrosative stress and decreased Cdc25A protein levels in a time-dependent and concentration-dependent manner. Similarly, iNOS-derived NO was sufficient to suppress Cdc25A expression, consistent with its role in mediating nitrosative stress. Whereas a decrease in Cdc25A half-life was not observed in response to SNCEE, we found the translational regulator eukaryotic initiation factor 2 (eIF2) was hyperphosphorylated and total protein translation was decreased with kinetics consistent with Cdc25A loss. Inhibition of eIF2 decreased Cdc25A levels, supporting the hypothesis that SNCEE suppressed Cdc25A translation through inhibition of eIF2. Nitrosative stress decreased the Cdc25A-bound fraction of apoptosis signal-regulating kinase-1 (ASK-1) and sensitized cells to apoptosis induced by the ASK-1–activating chemotherapeutic cis-diaminedichloroplatinum (II), suggesting that nitrosative stress–induced suppression of Cdc25A primed cells for ASK-1–dependent apoptosis. Together these data reveal novel NO-dependent enzymatic and translational mechanisms controlling Cdc25A, and implicate Cdc25A as a mediator of NO-dependent apoptotic signaling. [Cancer Res 2008;68(18):7457–65]