PP2C gamma is a splicing factor that dephosphorylates specific Substrates required for the formation of the spliceosome. In a previous study, we reported that the degradation of p21(Cip1/WAF1) was affected by PP2C gamma. causing an accumulation of cells in S phase. Here, we demonstrate that the PP2C gamma,induced degradation of p21(Cip1/WAF1) is mediated by Akt signaling. In cells expressing PP2C gamma. Akt1 protein was phosphorylated. When PP2C gamma expression was knocked down, the phosphorylation of Akt1 was reduced and the level of p21(Cip1/WAF1) protein was increased. Interestingly, the stability of p21(Cip1/WAF1) was highly maintained in Akt1-depleted cells despite the ectopic expression of PP2C gamma. Taken together, these results Suggest that PP2C gamma is a novel regulator Of p21(Cip1/WAF1) protein stability via the Akt signaling pathway. (C) 2009 Elsevier Inc. All rights reserved.