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Molecular and Cellular Biology, November 2003, p. 8110-8123, Vol. 23, No. 22
0270-7306/03/$08.00+0     DOI: 10.1128/MCB.23.22.8110-8123.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Identification of HiNF-P, a Key Activator of Cell Cycle-Controlled Histone H4 Genes at the Onset of S Phase

Partha Mitra,1 Rong-Lin Xie,1 Ricardo Medina,1 Hayk Hovhannisyan,1 S. Kaleem Zaidi,1 Yue Wei,2 J. Wade Harper,2 Janet L. Stein,1 André J. van Wijnen,1 and Gary S. Stein1*

Department of Cell Biology and Cancer Center, University of Massachusetts Medical School, Worcester, Massachusetts 01655,1 Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, Texas 770302

Received 16 May 2003/ Returned for modification 10 July 2003/ Accepted 7 August 2003

At the G1/S phase cell cycle transition, multiple histone genes are expressed to ensure that newly synthesized DNA is immediately packaged as chromatin. Here we have purified and functionally characterized the critical transcription factor HiNF-P, which is required for E2F-independent activation of the histone H4 multigene family. Using chromatin immunoprecipitation analysis and ligation-mediated PCR-assisted genomic sequencing, we show that HiNF-P interacts with conserved H4 cell cycle regulatory sequences in vivo. Antisense inhibition of HiNF-P reduces endogenous histone H4 gene expression. Furthermore, we find that HiNF-P utilizes NPAT/p220, a substrate of the cyclin E/cyclin-dependent kinase 2 (CDK2) kinase complex, as a key coactivator to enhance histone H4 gene transcription. The biological role of HiNF-P is reflected by impeded cell cycle progression into S phase upon antisense-mediated reduction of HiNF-P levels. Our results establish that HiNF-P is the ultimate link in a linear signaling pathway that is initiated with the growth factor-dependent induction of cyclin E/CDK2 kinase activity at the restriction point and culminates in the activation of histone H4 genes through HiNF-P at the G1/S phase transition.

* Corresponding author. Mailing address: Department of Cell Biology and Cancer Center, University of Massachusetts Medical School, 55 Lake Ave. North, Worcester, MA 01655-0106. Phone: (508) 856-5625. Fax: (508) 856-6800. E-mail: gary.stein{at}umassmed.edu.

Molecular and Cellular Biology, November 2003, p. 8110-8123, Vol. 23, No. 22
0022-538X/03/$08.00+0     DOI: 10.1128/MCB.23.22.8110-8123.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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