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.
Wolff
B
B
Max-Planck-Institut für Infektionsbiologie, Abteilung Molekulare Biologie, Berlin, Germany.
Naumann
M
M
D017487:Ankyrins; D002352:Carrier Proteins / Q000378:metabolism*; D018797:Cell Cycle Proteins; D051358:Cyclin-Dependent Kinase 4; D050762:Cyclin-Dependent Kinase Inhibitor p15; D019941:Cyclin-Dependent Kinase Inhibitor p16; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors*; D019942:Genes, p16; D006367:HeLa Cells; D006801:Humans; D016328:NF-kappa B / Q000378:metabolism*; D011485:Protein Binding; D011518:Proto-Oncogene Proteins; D020449:Repetitive Sequences, Amino Acid; D051996:Transcription Factor RelA; D014158:Transcription, Genetic; D015533:Transcriptional Activation; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D025521:Tumor Suppressor Proteins
D017487:Ankyrins; C493966:CDKN2B protein, human; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D050762:Cyclin-Dependent Kinase Inhibitor p15; D019941:Cyclin-Dependent Kinase Inhibitor p16; D016328:NF-kappa B; D011518:Proto-Oncogene Proteins; D051996:Transcription Factor RelA; D014409:Tumor Necrosis Factor-alpha; D025521:Tumor Suppressor Proteins; C495900:CDK4 protein, human; D051358:Cyclin-Dependent Kinase 4; D018844:Cyclin-Dependent Kinases