INK4 cell cycle inhibitors direct transcriptional inactivation of NF-kappaB

The nuclear factor kappa B, a transcription factor regulating the expressio n of multiple genes including genes essential for cell cycle control, is fo und in most cells in a dormant state in the cytoplasm bound to the inhibito ry family I kappa B via an ankyrin repeat domain. Stimulation of cells with a variety of inducers inactivates I kappa B proteins. The active dimeric N F-kappa B complex, often composed of 50- and 65-kilodalton subunits of the Rel family, translocates into the nucleus, where the NF-kappa Bp65 subunit stimulates transcription. Here me report that a family of proteins containi ng ankyrin repeats, the inhibitors of Cdk4 (INK4) is able to bind NF-kappa Bp65, The association of p161NK4 with NF-kappa Bp65 is considerable in HeLa - or 293 cells, if the NF-kappa B inhibitor I kappa B alpha is degraded in response to TNF alpha stimulation. Overexpression of INK4 molecules suppres ses the transactivational ability of NF-kappa B significantly, In contrast to INK4 proteins, the cell cycle inhibitor p27 enhances NF-kappa B transact ivation activity. Thus, the effect of INK4 proteins on NF-kappa B function possibly modifies NF-kappa B mediated transcriptional activation of cell cy cle associated factors.