The proteasome is a protein complex responsible for the degradation of polyubiquitin-tagged proteins. Besides the removal of target proteins, the proteasome also participates in the regulation of gene transcription in both proteolytic and non-proteolytic fashion. In this study the effect of proteasome inhibition on the basal expression of monocyte chemotactic protein-1 induced protein 1 (MCPIP1) was examined. Treatment of HepG2 or HeLa cells with proteasome inhibitor MG-132 resulted in a significant increase of MCPIP1 expression, both at mRNA and protein level. Interestingly, MG-132 did not alter MCPIP1 stability. Instead, the observed protein increase was blocked by actinomycin D, suggesting the involvement of de novo mRNA synthesis in the increase of MCPIP1 protein following MG-132 treatment. Using several inhibitors we determined the participation of extracellular-signal-regulated kinase 1/2 and p38 kinases in MCPIP1 upregulation by MG-132. Our findings show for the first time the impact of proteasome inhibition on MCPIP1 protein expression by modulation of the activity of intracellular signaling pathways. Overexpression of MCPIP1-myc protein decreased the viability of HeLa cells but not HepG2 cells, which correlates with the increased susceptibility of HeLa cells to MG-132 toxicity. Notably, both MG-132 treatment and MCPIP1-myc overexpression led to the activation of apoptosis, as revealed by the induction of caspases 3/7 in both types of cell lines. This suggests the involvement of MCPIP1 upregulation in toxic properties of proteasome inhibition, which is an acknowledged approach to the treatment of several cancer types.