We previously reported that knockdown of the farnesoid X receptor (FXR), a bile acid-activated nuclear receptor, increases mRNA level of cyclin-dependent kinase inhibitor p21/Cip1 in normal hepatocyte-derived cell line Fa2N-4 and hepatocellular carcinoma cell line HepG2. Although p21/Cip1 protein levels of HepG2 cells are also increased by FXR knockdown, elevated levels of p21/Cip1 mRNA does not cause an increase in p21/Cip1 protein levels of Fa2N-4 cells, indicating post-transcriptional suppression of p21/Cip1 expression in Fa2N-4 cells. Given that degradation of p21/Cip1 by proteasomes is mediated by PA28γ, an activator of the 20S proteasome, we examined whether p21/Cip1 regulates the expression of PA28γ, a proteasome activator, in HepG2 and Fa2N-4 cells. In Fa2N-4 cells, ectopic expression of p21/Cip1 increased the mRNA and protein levels of PA28γ. PA28γ expression was down-regulated by knockdown of p21/Cip1. In contrast, in HepG2 cells, neither ectopic expression nor knockdown of p21/Cip1 affected the expression of PA28γ. Therefore, p21/Cip1 likely down-regulates its own expression in a post-transcriptional manner by stimulating the expression of the proteasome activator PA28γ in normal hepatocyte-derived cells, while hepatocellular carcinoma cells lack such feedback regulation of p21/Cip1 expression.