the discodermia calyx toxin calyculin a enhances cyclin d1 phosphorylation and degradation, and arrests cell cycle progression in human breast cancer cellsdiscodermia花萼毒素calyculin有提高细胞周期蛋白d1磷酸化和退化,人类乳腺癌细胞细胞周期进程和逮捕.pdf

Toxins 2011, 3, 105-119; doi:10.3390/toxins3010105 OPEN ACCESS toxins ISSN 2072-6651 /journal/toxins Article The Discodermia calyx Toxin Calyculin A Enhances Cyclin D1 Phosphorylation and Degradation, and Arrests Cell Cycle Progression in Human Breast Cancer Cells Jessica R. Edelson and David L. Brautigan * Center for Cell Signaling and Department of Microbiology, University of Virginia School of Medicine, Charlottesville, VA 22908, USA; E-Mail: jrh9x@ * Author to whom correspondence should be addressed; E-Mail: db8g@; Tel.: +1-434-924-5892; Fax: +1-434-924-1236. Received: 8 October 2010; in revised form: 8 January 2011 / Accepted: 21 January 2011 / Published: 24 January 2011 Abstract: Cyclin D1 is a key regulator of the cell cycle that is over expressed in more than half of breast cancer patients. The levels of cyclin D1 are controlled primarily through post-translational mechanisms and phosphorylation of cyclin D1 at T286 induces its proteasomal degradation. To date, no studies have explored the involvement of phosphatases in this process. Here we treated human breast cancer cells with the structurally distinct toxins calyculin A, okadaic acid, and cantharidin, which are known to inhibit Ser/Thr phosphatases of the PPP family. At low nanomolar concentrations calyculin A induced T286 phosphorylation and degradation of cyclin D1 via the proteosome in MDA-MB-468 and MDA-MB-231 cells. Cyclin D1 degr