TGF-beta1 induction of p21WAF1/cip1 requires smad-independent protein kinase C signaling pathway.

Although it has been demonstrated that p21WAF1/Cip1 could be induced by transforming growth factor-beta1 (TGF-beta1) in a Smad-dependent manner, the cross-talk of Smad signaling pathway with other signaling pathways still remains poorly understood. In this study, we investigated a possible role of protein kinase C (PKC) signaling pathway in TGF-beta1 induction of p21WAF1/Cip1 in human keratinocytes HaCaT cells. Our data show that PKC is required for TGF-beta1 induction of p21WAF1/Cip1, as evidenced by the fact that specific inhibition of PKC leads to a decrease in p21WAF1/Cip1 protein and mRNA expression induced by TGF-beta1. And this notion is further supported by the observation that activation of p21WAF1/Cip1 promoter activity is dramatically attenu ated by treatment with PKC inhibitor. However, PKC signaling pathway is not associated with TGF-beta1 activation of Smad signaling pathway, because inhibition of PKC signaling pathway does not affect nuclear translocation of Smads induced by TGF-beta1. Taken together, our data suggest that PKC signaling pathway is required for p21WAF1/Cip1 expression by TGF-beta1, which is independent of Smad signaling pathway.