The HiNF-P/p220NPAT Cell Cycle Signaling Pathway Controls Nonhistone Target Genes

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Abstract
HiNF-P and its cofactor p220NPAT are principal factors regulating histone gene expression at the G1-S phase cell cycle transition. Here, we have investigated whether HiNF-P controls other cell cycle– and cancer-related genes. We used cDNA microarrays to monitor responsiveness of gene expression to small interfering RNA–mediated depletion of HiNF-P. Candidate HiNF-P target genes were examined for the presence of HiNF-P recognition motifs, in vitro HiNF-P binding to DNA, and in vivo association by chromatin immunoprecipitations and functional reporter gene assays. Of 177 proliferation-related genes we tested, 20 are modulated in HiNF-P–depleted cells and contain putative HiNF-P binding motifs. We validated that at least three genes (i.e., ATM, PRKDC, and CKS2) are HiNF-P dependent and provide data indicating that the DNA damage response is altered in HiNF-P–depleted cells. We conclude that, in addition to histone genes, HiNF-P also regulates expression of nonhistone targets that influence competency for cell cycle progression. [Cancer Res 2007;67(21):10334–42]