Deregulated expression of cyclin D1 overrides antimitogenic signals

Several types of epithelial neoplasms exhibit high expression of transforming growth factor β1 (TGF(β)-1), indicating that they have acquired tolerance to this normally growth inhibitory cytokine. Since cyclin D1 is expressed at high levels in murine skin tumors coincident with high levels of TGF(β)-1 expression, we hypothesized that cyclin D1 may override TGF(β)-1 induced growth arrest. We observed that in primary murine keratinocytes treated with TGF(β)-1, cyclin D1 is quickly suppressed at both the mRNA and protein level. Since changes in other cell cycle proteins occur at a later time during TGF(β)-1 treatment, the early suppression of cyclin D1 suggests that this gene is a critical target for TGF(β)-1 growth suppression. Using primary keratinocytes from transgenic mice that overexpress cyclin D1 (K5-D1 mice), we observed partial resistance to TGF(β)-1 growth inhibition. This resistance involves changes in the cyclin/cdk/inhibitor complexes rather than differences in expression of the TGF(β) receptors or signaling. Comparison of cdk associated kinase activity between wild-type and K5-D1 cells shows differential regulation. We conclude that deregulated cyclin D1 and subsequent alterations in cell cycle machinery provides keratinocytes the ability to at least partially override growth inhibitory signals.