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Molecular and Cellular Biology, March 2009, p. 1123-1133, Vol. 29, No. 5
0270-7306/09/$08.00+0     doi:10.1128/MCB.00841-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Postrecruitment Regulation of RNA Polymerase II Directs Rapid Signaling Responses at the Promoters of Estrogen Target Genes ^,

Miltiadis Kininis,^1,2 Gary D. Isaacs,^1,3 Leighton J. Core,^1,3 Nasun Hah,^1,3 and W. Lee Kraus^1,2,3,4*

Department of Molecular Biology and Genetics, Cornell University, Ithaca, New York 14853,¹ Graduate Field of Genetics and Development, Cornell University, Ithaca, New York 14853,² Graduate Field of Biochemistry, Molecular and Cell Biology, Cornell University, Ithaca, New York 14853,³ Department of Pharmacology, Weill Medical College of Cornell University, New York, New York 10021⁴

Received 26 May 2008/ Returned for modification 27 June 2008/ Accepted 9 December 2008

Under classical models for signal-dependent transcription in eukaryotes, DNA-binding activator proteins regulate the recruitment of RNA polymerase II (Pol II) to a set of target promoters. However, recent studies, as well as our results herein, show that Pol II is widely distributed (i.e., "preloaded") at the promoters of many genes prior to specific signaling events. How Pol II recruitment and Pol II preloading fit within a unified model of gene regulation is unclear. In addition, the mechanisms through which cellular signals activate preloaded Pol II across mammalian genomes remain largely unknown. We show here that the predominant genomic outcome of estrogen signaling is the postrecruitment regulation of Pol II activity at target gene promoters, likely through specific changes in Pol II phosphorylation rather than through recruitment of Pol II to the promoters. Furthermore, we show that negative elongation factor binds to estrogen target promoters in conjunction with preloaded Pol II and represses gene expression until the appropriate signal is received. Finally, our studies reveal that the estrogen-dependent activation of preloaded Pol II facilitates rapid gene regulatory responses which play important physiological roles in regulating estrogen signaling itself. Our results reveal a broad use of postrecruitment Pol II regulation by the estrogen signaling pathway, a mode of regulation that is likely to apply to a wide variety of signal-regulated pathways.

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* Corresponding author. Mailing address: Department of Molecular Biology and Genetics, Cornell University, 465 Biotechnology Building, Ithaca, NY 14853. Phone: (607) 255-6087. Fax: (607) 255-6249. E-mail: wlk5{at}cornell.edu

Published ahead of print on 22 December 2008.

Supplemental material for this article may be found at http://mcb.asm.org/.

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Molecular and Cellular Biology, March 2009, p. 1123-1133, Vol. 29, No. 5
0270-7306/09/$08.00+0     doi:10.1128/MCB.00841-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

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