INK4 cell cycle inhibitors direct transcriptional inactivation of NF-κB

Abstract

The nuclear factor κB, 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 IκB via an ankyrin repeat domain. Stimulation of cells with a variety of inducers inactivates IκB proteins. The active dimeric NF-κB complex, often composed of 50- and 65-kilodalton subunits of the Rel family, translocates into the nucleus, where the NF-κBp65 subunit stimulates transcription. Here we report that a family of proteins containing ankyrin repeats, the inhibitors of Cdk4 (INK4) is able to bind NF-κBp65. The association of p16INK4 with NF-κBp65 is considerable in HeLa- or 293 cells, if the NF-κB inhibitor IκBα is degraded in response to TNFα stimulation. Overexpression of INK4 molecules suppresses the transactivational ability of NF-κB significantly. In contrast to INK4 proteins, the cell cycle inhibitor p27 enhances NF-κB transactivation activity. Thus, the effect of INK4 proteins on NF-κB function possibly modifies NF-κB mediated transcriptional activation of cell cycle associated factors.