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Blood, 1 September 2008, Vol. 112, No. 5, pp. 1960-1970. Prepublished online as a Blood First Edition Paper on June 17, 2008; DOI 10.1182/blood-2007-09-113860. This Article Full Text (PDF) Supplemental Figures All Versions of this Article: blood-2007-09-113860v1 112/5/1960    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 Agarwal, A. Articles by Deininger, M. W Search for Related Content PubMed PubMed Citation Articles by Agarwal, A. Articles by Deininger, M. W Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted September 20, 2007 Accepted April 20, 2008 Absence of SKP2 expression attenuates BCR-ABL-induced myeloproliferative disease Anupriya Agarwal, Thomas GP Bumm, Amie S Corbin, Thomas O'Hare, Marc Loriaux, Jonathan VanDyke, Stephanie G Willis, Jutta Deininger, Keiichi I Nakayama, Brian J Druker, and Michael W Deininger* Division of Hematology & Oncology, Oregon Health & Science University, Portland, OR, United States Howard Hughes Medical Institute, Oregon Health & Science University, Portland, OR, United States Department of Pathology, Oregon Health & Science University, Portland, OR, United States Department of Molecular and Cellular Biology, Kyushu University, Fukuoka, Japan * Corresponding author; email: deininge{at}ohsu.edu. BCR-ABL is proposed to impair cell cycle control by disabling p27, a tumor suppressor that inhibits cyclin-dependent kinases. We show that in cell lines p27 expression is inversely correlated with expression of SKP2, the F-box protein of SCFSKP2, the E3 ubiquitin ligase that promotes proteasomal degradation of p27. Inhibition of BCR-ABL kinase causes G1 arrest, downregulation of SKP2 and accumulation of p27. Ectopic expression of wildtype SKP2, but not a mutant unable to recognize p27, partially rescues cell cycle progression. A similar regulation pattern is seen in cell lines transformed by FLT3-ITD, JAK2V617F and TEL-PDGFR suggesting that the SKP2/p27 conduit may be a universal target for leukemogenic tyrosine kinases. Mice transplanted with BCR-ABL-infected SKP2-/- marrow developed a myeloproliferative syndrome but survival was significantly prolonged compared to recipients of BCR-ABL-expressing SKP2+/+ marrow. SKP2-/- leukemic cells demonstrated higher levels of nuclear p27 than SKP2+/+ counterparts, suggesting that the attenuation of leukemogenesis depends on increased p27 expression. Our data identify SKP2 as a crucial mediator of BCR-ABL-induced leukemogenesis and provide the first in vivo evidence that SKP2 promotes oncogenesis. Hence stabilization of p27 by inhibiting its recognition by SCFSKP2 may be therapeutically useful. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: J. Xiao, S. Yin, Y. Li, S. Xie, D. Nie, L. Ma, X. Wang, Y. Wu, and J. Feng SKP2 siRNA inhibits the degradation of P27kip1 and down-regulates the expression of MRP in HL-60/A cells Acta Biochim Biophys Sin, August 1, 2009; 41(8): 699 - 708. [Abstract] [Full Text] [PDF]

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