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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. This Article Full Text Full Text (PDF) All Versions of this Article: blood-2006-11-060350v1 110/5/1631    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 Lwin, T. Articles by Tao, J. Search for Related Content PubMed PubMed Citation Articles by Lwin, T. Articles by Tao, J. Related Collections Neoplasia Cell Cycle Cell Adhesion and Motility Oncogenes and Tumor Suppressors Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  NEOPLASIA Cell adhesion induces p27Kip1-associated cell-cycle arrest through down-regulation of the SCFSkp2 ubiquitin ligase pathway in mantle-cell and other non-Hodgkin B-cell lymphomas Tint Lwin1, Lori A. Hazlehurst1, Sophie Dessureault1, Raymond Lai2, Wenlong Bai1, Eduardo Sotomayor1, Lynn C. Moscinski1, William S. Dalton1, and Jianguo Tao1 1 Department of Interdisciplinary Oncology and Experimental Therapeutics Program, H. Lee Moffitt Cancer Center and Research Institute at the University of South Florida, Tampa; 2 Department of Laboratory Medicine and Pathology, Cross Cancer Institute, University of Alberta, Edmonton, Canada Mounting evidence suggests that dynamic interactions between a 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 that adhesion of MCL and other non-Hodgkin lymphoma (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 the Skp2/p27Kip1 signaling pathway. Overall, this report, for the first time, demonstrates that cell-cell contact controls the tumor cell cycle via ubiquitin-proteasome proteolytic pathways in MCL and other NHLs. The understanding of this novel molecular pathway may prove valuable in designing new therapeutic approaches for modifying tumor cell growth and response to therapy. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: S. Uddin, M. Ahmed, P. Bavi, R. El-Sayed, N. Al-Sanea, A. AbdulJabbar, L. H. Ashari, S. Alhomoud, F. Al-Dayel, A. R. Hussain, et al. Bortezomib (Velcade) Induces p27Kip1 Expression through S-Phase Kinase Protein 2 Degradation in Colorectal Cancer Cancer Res., May 1, 2008; 68(9): 3379 - 3388. [Abstract] [Full Text] [PDF] M. B. Meads, L. A. Hazlehurst, and W. S. Dalton The Bone Marrow Microenvironment as a Tumor Sanctuary and Contributor to Drug Resistance Clin. Cancer Res., May 1, 2008; 14(9): 2519 - 2526. [Abstract] [Full Text] [PDF] 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] O. A. O'Connor Mantle Cell Lymphoma: Identifying Novel Molecular Targets in Growth and Survival Pathways Hematology, January 1, 2007; 2007(1): 270 - 276. [Abstract] [Full Text] [PDF]

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