AbstractCell cycle progression beyond the G1/S phase transition requires the activation of a transcription complex containing histone nuclear factor P (HiNF‐P) and nuclear protein mapped to ataxia telangiectasia (p220NPAT) in response to cyclin dependent kinase 2 (CDK2)/cyclin E signaling. We show here that the potent co‐activating properties of HiNF‐P/p220NPAT on the histone H4 gene promoter, which are evident in the majority of human cell types, are sporadically neutralized in distinct somatic cell lines. In cells where HiNF‐P and p220NPAT do not activate the H4 gene promoter, HiNF‐P instead represses transcription. Our data suggest that the cell type specific expression of the cyclin‐dependent kinase inhibitory (CKI) protein p57KIP2 inhibits the HiNF‐P dependent activation of the histone H4 promoter. We propose that, analogous to E2F proteins and other cell cycle regulatory proteins, HiNF‐P is a bifunctional transcriptional regulator that can activate or repress cell cycle controlled genes depending on the cellular context. J. Cell. Biochem. 101: 181–191, 2007. © 2006 Wiley‐Liss, Inc.