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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, 2007February 15, 2007; DOI 10.1182/blood-2006-07-038703.
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Submitted July 31, 2006
Accepted January 22, 2007
CKS1B, over expressed in aggressive disease, regulates multiple myeloma growth and survival through SKP2- and p27Kip1-dependent and independent mechanisms
Fenghuang Zhan, Simona Colla, Xiaosong Wu, James P Stewart, W. Michael Kuehl, Bart Barlogie, and John D. Shaughnessy Jr.*
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
Genetics Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD
* Corresponding author; email: shaughnessyjohn{at}uams.edu.
Over expression of CKS1B, a gene mapping within a minimally amplified region between 153-154Mb 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. Utilizing four 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 non-degradable form of p27Kip1 (p27T187A) lead to cell cycle arrest apoptosis was modest. Importantly, while knock down of SKP2 or over expression of p27T187A induced cell cycle arrest in KMS28PE, a 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.
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