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Molecular and Cellular Biology, March 2008, p. 1630-1643, Vol. 28, No. 5
0270-7306/08/$08.00+0     doi:10.1128/MCB.01767-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Up-Regulation of P-TEFb by the MEK1-Extracellular Signal-Regulated Kinase Signaling Pathway Contributes to Stimulated Transcription Elongation of Immediate Early Genes in Neuroendocrine Cells{triangledown} ,{dagger}

Toshitsugu Fujita, Stephan Ryser,{ddagger} Isabelle Piuz, and Werner Schlegel*

Fondation pour Recherches Médicales, Medical Faculty, University of Geneva, 64 av. de la Roseraie, 1211 Geneva, Switzerland

Received 26 September 2007/ Accepted 7 December 2007

The positive elongation factor P-TEFb appears to function as a crucial C-terminal-domain (CTD) kinase for RNA polymerase II (Pol II) transcribing immediate early genes (IEGs) in neuroendocrine GH4C1 cells. Chromatin immunoprecipitation indicated that in resting cells Pol II occupied the promoter-proximal regions of the c-fos and junB genes, together with the negative elongation factors DSIF and NELF. Thyrotropin-releasing hormone (TRH)-induced recruitment of positive transcription elongation factor b (P-TEFb) abolished the pausing of Pol II and enhanced phosphorylation of CTD serine 2, resulting in transcription elongation. In addition, P-TEFb was essential for splicing and 3'-end processing of IEG transcripts. Importantly, the MEK1-extracellular signal-regulated kinase (ERK) signaling pathway activated by TRH up-regulated nuclear CDK9 and CDK9/cyclinT1 dimers (i.e., P-TEFb), facilitating the recruitment of P-TEFb to c-fos and other IEGs. Thus, in addition to established gene transcription control via promoter response elements, the MEK1-ERK signaling pathway controls transcription elongation by Pol II via the up-regulation of nuclear CDK9 integrated into P-TEFb.

* Corresponding author. Mailing address: Fondation pour Recherches Médicales, 64 av. de la Roseraie, University of Geneva, 1211 Geneva, Switzerland. Phone: 41-22-3823811. Fax: 41-22-3475979. E-mail: werner.schlegel{at}medecine.unige.ch

{triangledown} Published ahead of print on 17 December 2007.

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

{ddagger} Present address: Laboratory of Molecular Gynecology and Obstetrics, Department of Gynecology and Obstetrics, University Hospital of Geneva, Geneva, Switzerland.

Molecular and Cellular Biology, March 2008, p. 1630-1643, Vol. 28, No. 5
0270-7306/08/$08.00+0     doi:10.1128/MCB.01767-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



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