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Prepublished online as a Blood First Edition Paper on July 10, 2003; DOI 10.1182/blood-2003-04-1027. This Article Full Text (PDF) All Versions of this Article: 2003-04-1027v1 102/9/3179    most recent 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 Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Deng, X. Articles by May, W. S. Search for Related Content PubMed PubMed Citation Articles by Deng, X. Articles by May, W. S. Social Bookmarking                   What's this? Submitted April 3, 2003 Accepted July 2, 2003 Bcl2 retards G1/S cell cycle transition by regulating intracellular ROS Xingming Deng, Fengqin Gao, and William Stratford May* Shands Cancer Center, University of Florida, Gainesville, FL, USA * Corresponding author; email: smay{at}ufscc.ufl.edu. Antiapoptotic function of Bcl2 is regulated by phosphorylation. Bcl2 also regulates cell cycle progression but the molecular mechanism is unclear. Bcl2 is functionally expressed in mitochondria where it can act as an antioxidant that may regulate intracellular reactive oxygen species (ROS). Since ROS have been reported to act as second messengers in cell signaling, we tested whether Bcl2 phosphorylation regulates ROS and cell cycle progression. G1 S transition and ROS levels were measured in cells expressing either the gain of function phosphomimetic Bcl2 mutants S70E and T69E/S70E/S87E (EEE) or the non-phosphorylatable and survival-deficient mutants S70A and T69A/S70A/S87A (AAA). Expression of S70E and EEE but not the A-containing Bcl2 mutants retards G1 S transition by 35-50% and significantly slows cell growth in association with reduced levels of intracellular ROS. In addition to expression of the phosphomimetic Bcl2 mutants, either IL3 withdrawal or treatment of cells with the antioxidant pyrrolidine dithiocarbamate (PDTC) also reduces intracellular ROS levels in association with up-regulation of p27 and accumulation of cells in G0/G1. Retardation of G1 S transition can be overridden by directly adding H2O2 to the cells in a mechanism that involves down-regulation of p27 and activation of Cdk2. Thus, Bcl2 may regulate G1 S transition by a novel signaling mechanism that couples regulation of intracellular ROS with p27 and Cdk2. Furthermore, phosphorylation of Bcl2 may functionally link its antiapoptotic, cell cycle retardation and antioxidant properties. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? 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