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Blood, 1 May 2008, Vol. 111, No. 9, pp. 4690-4699. Prepublished online as a Blood First Edition Paper on February 27, 2008; DOI 10.1182/blood-2007-09-112904. This Article Full Text Full Text (PDF) Supplemental Figure All Versions of this Article: blood-2007-09-112904v1 111/9/4690    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map 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 CrossRef Google Scholar Articles by Chen, Q. Articles by Orlowski, R. Z. PubMed PubMed Citation Articles by Chen, Q. Articles by Orlowski, R. Z. Related Collections Cell Cycle Neoplasia Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  NEOPLASIA Targeting the p27 E3 ligase SCFSkp2 results in p27- and Skp2-mediated cell-cycle arrest and activation of autophagy Qing Chen1, Weilin Xie2, Deborah J. Kuhn1, Peter M. Voorhees1,3, Antonia Lopez-Girona2, Derek Mendy2, Laura G. Corral2, Veronique Plantevin Krenitsky2, Weiming Xu2, Laure Moutouh-de Parseval2, David R. Webb2, Frank Mercurio2, Keiichi I. Nakayama4, Keiko Nakayama5, and Robert Z. Orlowski1,3,6 1 Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill; 2 Celgene Signal Research Division, San Diego, CA; 3 Department of Pharmacology, University of North Carolina at Chapel Hill; 4 Department of Molecular and Cellular Biology, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan; 5 Division of Developmental Genetics, Tohoku University Graduate School of Medicine, Miyagi, Japan; and 6 Department of Medicine, Division of Hematology/Oncology, University of North Carolina at Chapel Hill Decreased p27Kip1 levels are a poor prognostic factor in many malignancies, and can occur through up-regulation of SCFSkp2 E3 ligase function, resulting in enhanced p27 ubiquitination and proteasome-mediated degradation. While proteasome inhibitors stabilize p27Kip1, agents inhibiting SCFSkp2 may represent more directly targeted drugs with the promise of enhanced efficacy and reduced toxicity. Using high-throughput screening, we identified Compound A (CpdA), which interfered with SCFSkp2 ligase function in vitro, and induced specific accumulation of p21 and other SCFSkp2 substrates in cells without activating a heat-shock protein response. CpdA prevented incorporation of Skp2 into the SCFSkp2 ligase, and induced G1/S cell-cycle arrest as well as SCFSkp2- and p27-dependent cell killing. This programmed cell death was caspase-independent, and instead occurred through activation of autophagy. In models of multiple myeloma, CpdA overcame resistance to dexamethasone, doxorubicin, and melphalan, as well as to bortezomib, and also acted synergistically with this proteasome inhibitor. Importantly, CpdA was active against patient-derived plasma cells and both myeloid and lymphoblastoid leukemia blasts, and showed preferential activity against neoplastic cells while relatively sparing other marrow components. These findings provide a rational framework for further development of SCFSkp2 inhibitors as a novel class of antitumor agents. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

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