INK4 cell cycle inhibitors direct transcriptional inactivation of NF-kappaB.

The nuclear factor kappaB, a transcription factor regulating the expression of multiple genes including genes essential for cell cycle control, is found in most cells in a dormant state in the cytoplasm bound to the inhibitory family I kappaB via an ankyrin repeat domain. Stimulation of cells with a variety of inducers inactivates I kappaB proteins. The active dimeric NF-kappaB complex, often composed of 50- and 65-kilodalton subunits of the Rel family, translocates into the nucleus, where the NF-kappaBp65 subunit stimulates transcription. Here we report that a family of proteins containing ankyrin repeats, the inhibitors of Cdk4 (INK4) is able to bind NF-kappaBp65. The association of p16INK4 with NF-kappaBp65 is considerable in HeLa- or 293 cells, if the NF-kappaB inhibitor I kappaB alpha is degraded in response to TNFalpha stimulation. Overexpression of INK4 molecules suppresses the transactivational ability of NF-kappaB significantly. In contrast to INK4 proteins, the cell cycle inhibitor p27 enhances NF-kappaB transactivation activity. Thus, the effect of INK4 proteins on NF-kappaB function possibly modifies NF-kappaB mediated transcriptional activation of cell cycle associated factors.