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 p27^Kip1 and p21 (WAF1) proteins. The adhesion-mediated p27^Kip1 and p21 increases were posttranslationally regulated via the down-regulation of Skp2, a subunit of SCF^Skp2 ubiquitin ligase. Overexpression of Skp2 in MCL decreased p27^Kip1, whereas inhibition of Skp2 by siRNA increased p27^Kip1 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 p27^Kip1 degradation, thus implicating Cdh1 as an upstream effector of the Skp2/p27^Kip1 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.