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A more recent version of this article appeared on April 1, 2004
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Submitted on October 12, 2003
Revised on December 22, 2003
Accepted on January 9, 2004
1 Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC 27710
* Corresponding author. E-mail address: means001{at}mc.duke.edu.
Calcium (Ca2+) and calmodulin (CaM) are required for progression of mammalian cells from quiescence into S phase. In multiple cell types, cyclosporin A causes a G1 cell cycle arrest, implicating the serine/threonine phosphatase calcineurin as one Ca2+/CaM-dependent enzyme required for G1 transit. Here we show, in diploid human fibroblasts, that cyclosporin A arrested cells in G1 before cyclin D/cdk4 complex activation and retinoblastoma (pRb) hyperphosphorylation. This arrest occurred in early G1 with low levels of cyclin D1 protein. Since cyclin D1 mRNA was induced normally in the cyclosporin A treated cells, we analyzed the half-life of cyclin D1 in the presence of cyclosporin A and found no difference from control cells. However, cyclosporin A treatment dramatically reduced cyclin D1 protein synthesis. Although these pharmacological experiments suggested that calcineurin regulates cyclin D1 synthesis, we evaluated the effects of overexpression of activated calcineurin on cyclin D1 synthesis. In contrast to the reduction of cyclin D1 with cyclosporin A, ectopic expression of calcium/calmodulin-independent calcineurin promoted synthesis of cyclin D1 during G1 progression. Therefore, calcineurin is a Ca2+/CaM-dependent target that regulates cyclin D1 accumulation in G1.
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