A skin-specific block in NF-kappaB signaling leads to hyperproliferation of the keratinocytes, inflammation, and spontaneous development of squamous cell carcinoma (SCC). Here we show that an inhibition of NF-kappaB signaling in keratinocytes, via the expression of the super-repressor/ degradation-resistant form of the IkappaBalpha protein (IkappaBalphaDN), interferes with the growth arrest induced by the tumor promoter 12-O-tetradecanoylphorbol 13-acetate (TPA). The IkappaBalphaDN cells are able to overcome the TPA-induced cell cycle block. Although SCC development as well as hyperproliferation due to IkappaBalphaDN expression in keratinocytes is known to require TNFR1 signaling, the effect of IkappaBalphaDN on phorbol ester signaling is downstream/independent of TNFR1. These data thus identify an interaction between IkappaBalphaDN and the tumor promoter TPA in the growth regulation of keratinocytes. The proposed mechanism is also likely to be significant in the process of cancer development due to NF-kappaB inhibition.