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Blood, 1 September 2007, Vol. 110, No. 5, pp. 1631-1638.
Prepublished online as a Blood First Edition Paper on May 14, 2007; DOI 10.1182/blood-2006-11-060350.
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Submitted November 28, 2006
Accepted May 13, 2007
Cell adhesion induces p27Kip1-associated cell-cycle arrest through down-regulation of the SCFSkp2 ubiquitin ligase pathway in mantle cell and other non-Hodgkin's B-cell lymphomas
Tint Lwin, Lori A Hazlehurst, Sophie Dessureault, Raymond Lai, Wenlong Bai, Eduardo Sotomayor, Lynn C Moscinski, William S Dalton, and Jianguo Tao*
Dept of Interdisciplinary Oncology & Exper. Therapeutics, H. Lee Moffitt Cancer Center & Research Institute, University of South Florida, Tampa, FL, United States
Department of Laboratory Medicine and Pathology, Cross Cancer Institute, University of Alberta, Edmonton, Alberta, Canada
* Corresponding author; email: taoj{at}moffitt.usf.edu.
Mounting evidence suggests that dynamic interactions between tumor and its microenvironment play a critical role in tumor development, cell cycle progression and response to therapy. In this study we used mantle cell lymphoma (MCL) as a model to characterize the mechanisms by which stroma regulate cell-cycle progression. We demonstrated adhesion of MCL and other non-Hodgkin lymphomas (NHL) cells to bone marrow stromal cells resulted in a reversible G1 arrest associated with elevated p27Kip1 and p21(WAF1) proteins. The adhesion mediated p27Kip1 and p21 increases were posttranslationally regulated via the down-regulation of Skp2, a subunit of SCFSkp2 ubiquitin ligase. Overexpression of Skp2 in MCL decreased p27Kip1, whereas inhibition of Skp2 by siRNA increased p27Kip1 and p21 levels. Furthermore, we found cell adhesion up-regulated Cdh1 (an activating subunit of anaphase-promoting complex (APC) ubiquitin ligase), and reduction of Cdh1 by siRNA induced Skp2 accumulation, and hence p27Kip1 degradation, thus implicating Cdh1 as an upstream effector of Skp2/p27Kip1 signaling pathway. Overall, this report, for the first time, demonstrates that cell-cell contact controls tumor cell cycle via ubiquitin-proteasome proteolytic pathways in MCL and other NHL. The understanding of this novel molecular pathway may prove valuable in designing new therapeutic approaches for modifying tumor cell growth and response to therapy.
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