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Molecular and Cellular Biology, April 2003, p. 2821-2833, Vol. 23, No. 8
0270-7306/03/$08.00+0     DOI: 10.1128/MCB.23.8.2821-2833.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

NPAT Expression Is Regulated by E2F and Is Essential for Cell Cycle Progression

Department of Biomedical Genetics, University of Rochester, Rochester, New York 14642,¹ Department of Experimental Oncology, European Institute of Oncology, 20141 Milan, Italy,² Massachusetts General Hospital Cancer Center, Charlestown, Massachusetts 02129,³ Frontier Research Center, National Institute of Radiological Science, Inage-ku, Chiba 263, Japan⁴

Received 5 September 2002/ Returned for modification 16 October 2002/ Accepted 11 January 2003

NPAT is an in vivo substrate of cyclin E-Cdk2 kinase and is thought to play a critical role in coordinated transcriptional activation of histone genes during the G₁/S-phase transition and in S-phase entry in mammalian cells. Here we show that NPAT transcription is up-regulated at the G₁/S-phase boundary in growth-stimulated cells and that the NPAT promoter responds to activation by E2F proteins. We demonstrate that endogenous E2F proteins interact with the promoter of the NPAT gene in vivo and that induced expression of E2F1 stimulates NPAT mRNA expression, supporting the idea that the expression of NPAT is regulated by E2F. Consistently, we find that the E2F sites in the NPAT promoter are required for its activation during the G₁/S-phase transition. Moreover, we show that the expression of NPAT accelerates S-phase entry in cells released from quiescence. The inhibition of NPAT expression by small interfering RNA duplexes impedes cell cycle progression and histone gene expression in tissue culture cells. Thus, NPAT is an important E2F target that is required for cell cycle progression in mammalian cells. As NPAT is involved in the regulation of S-phase-specific histone gene transcription, our findings indicate that NPAT links E2F to the activation of S-phase-specific histone gene transcription.

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