The p38 mitogen-activated protein kinase (MAPK) is a key mediator of stress, extracellular-, growth factor-, and cytokine-induced signaling and has been implicated in the development of cancer. Our previous work showed evidence for p38 MAPK activation in a subset of transformed follicular lymphomas (Elenitoba-Johnson et al. Proc. Natl. Acad. Sci. U.S.A. 2003. 100:7259). We demonstrated that inhibition of p38 MAPK by SB203580 resulted in dose- and time-dependent caspase-3-mediated apoptosis. In order to further elucidate the basis of the cellular effects of SB203580, we have employed a systems biologic approach involving cDNA microarray and quantitative proteomic analysis of transformed follicular lymphoma derived-cells (OCI-Ly1) treated with SB203580. Gene expression profiling revealed differential expression (>1.5-fold) of 374 genes/ESTs in cells treated for 3 hours, and 515 genes/ESTs in cells treated for 21 hours. The majority (52% at 3 hours and 91% at 21 hours) were downregulated, including genes encoding growth cytokines, transcriptional regulators and cytoskeletal proteins. Quantitative proteomic analysis using ICATTM-LC/MS/MS identified 277 differentially expressed proteins at 3 hours and 350 proteins at 21 hours of treatment with SB203580, the majority of which were also downregulated. Analysis of functional groups of the differentially expressed proteins implicated components of diverse overlapping pathways including the IL-6/PI-3K, IGF-2/Ras/Raf, WNT8d/Frizzled, MAPKAPK-2 and NFB. The differential phosphorylation status of selected kinase-active proteins was validated by western blotting analysis. Our complementary genomic and proteomic approach reveal the global cellular consequences of SB203580 treatment and provide insights into its growth inhibitory effect on transformed follicular lymphoma cells.