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Blood, 1 June 2007, Vol. 109, No. 11, pp. 4995-5001. Prepublished online as a Blood First Edition Paper on March 15, 2007; DOI 10.1182/blood-2006-07-038703. This Article Full Text Full Text (PDF) All Versions of this Article: blood-2006-07-038703v1 blood-2006-07-038703v2 109/11/4995    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 HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Zhan, F. Articles by Shaughnessy, J. D. Search for Related Content PubMed PubMed Citation Articles by Zhan, F. Articles by Shaughnessy, J. D., Jr Related Collections Neoplasia Apoptosis Cell Cycle Oncogenes and Tumor Suppressors Related Article in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  NEOPLASIA CKS1B, overexpressed in aggressive disease, regulates multiple myeloma growth and survival through SKP2- and p27Kip1-dependent and -independent mechanisms Fenghuang Zhan1, Simona Colla1, Xiaosong Wu1, Bangzheng Chen1, James P. Stewart1, W. Michael Kuehl2, Bart Barlogie1, and John D. Shaughnessy, Jr1 1 Donna D. and Donald M. Lambert Laboratory of Myeloma Genetics at the Myeloma Institute for Research and Therapy, University of Arkansas for Medical Sciences, Little Rock, AR; 2 Genetics Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD Overexpression of CKS1B, a gene mapping within a minimally amplified region between 153 to 154 Mb of chromosome 1q21, is linked to a poor prognosis in multiple myeloma (MM). CKS1B binds to and activates cyclin-dependent kinases and also interacts with SKP2 to promote the ubiquitination and proteasomal degradation of p27Kip1. Overexpression of CKS1B or SKP2 contributes to increased p27Kip1 turnover, cell proliferation, and a poor prognosis in many tumor types. Using 4 MM cell lines harboring MAF-, FGFR3/MMSET-, or CCND1-activating translocations, we show that lentiviral delivery of shRNA directed against CKS1B resulted in ablation of CKS1B mRNA and protein with concomitant stabilization of p27Kip1, cell cycle arrest, and apoptosis. Although shRNA-mediated knockdown of SKP2 and forced expression of a nondegradable form of p27Kip1 (p27T187A) led to cell cycle arrest, apoptosis was modest. Of importance, while knockdown of SKP2 or overexpression of p27T187A induced cell cycle arrest in KMS28PE, an MM cell line with biallelic deletion of CDKN1B/p27Kip1, CKS1B ablation induced strong apoptosis. These data suggest that CKS1B influences myeloma cell growth and survival through SKP2- and p27Kip1-dependent and -independent mechanisms and that therapeutic strategies aimed at abolishing CKS1B function may hold promise for the treatment of high-risk disease for which effective therapies are currently lacking. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? Related Article in Blood Online: A validated gene expression model of high-risk multiple myeloma is defined by deregulated expression of genes mapping to chromosome 1 John D. Shaughnessy, Jr, Fenghuang Zhan, Bart E. Burington, Yongsheng Huang, Simona Colla, Ichiro Hanamura, James P. Stewart, Bob Kordsmeier, Christopher Randolph, David R. Williams, Yan Xiao, Hongwei Xu, Joshua Epstein, Elias Anaissie, Somashekar G. Krishna, Michele Cottler-Fox, Klaus Hollmig, Abid Mohiuddin, Mauricio Pineda-Roman, Guido Tricot, Frits van Rhee, Jeffrey Sawyer, Yazan Alsayed, Ronald Walker, Maurizio Zangari, John Crowley, and Bart Barlogie Blood 2007 109: 2276-2284. [Abstract] [Full Text] [PDF] This article has been cited by other articles: Q. Chen, W. Xie, D. J. Kuhn, P. M. Voorhees, A. Lopez-Girona, D. Mendy, L. G. Corral, V. P. Krenitsky, W. Xu, L. Moutouh-de Parseval, et al. Targeting the p27 E3 ligase SCFSkp2 results in p27- and Skp2-mediated cell-cycle arrest and activation of autophagy Blood, May 1, 2008; 111(9): 4690 - 4699. [Abstract] [Full Text] [PDF] K. Mahtouk, D. Hose, J. De Vos, J. Moreaux, M. Jourdan, J. F. Rossi, T. Reme, H. Goldschmidt, and B. Klein Input of DNA Microarrays to Identify Novel Mechanisms in Multiple Myeloma Biology and Therapeutic Applications Clin. Cancer Res., December 15, 2007; 13(24): 7289 - 7295. [Abstract] [Full Text] [PDF]

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