Nucleic Acids Research Advance Access originally published online on January 26, 2007
Nucleic Acids Research 2007 35(3):1007-1017; doi:10.1093/nar/gkl1138
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Nucleic Acids Research, 2007, Vol. 35, No. 3 1007-1017
© 2007 The Author(s)
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.0/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Molecular Biology |
Gene-specific recruitment of positive and negative elongation factors during stimulated transcription of the MKP-1 gene in neuroendocrine cells
1Fondation pour Recherches Médicales, University of Geneva, 64 av. de la Roseraie, 1211 Geneva, Switzerland
*To whom correspondence should be addressed. Tel: +41 22 3823811; Fax: +41 22 3475979; Email: werner.schlegel{at}medecine.unige.ch
Received October 5, 2006. Revised December 14, 2006. Accepted December 14, 2006.
MAP kinase phosphatase-1 (MKP-1) controls nuclear MAP kinase activity with important consequences on cell growth or apoptosis. MKP-1 transcription is initiated constitutively but elongation is blocked within exon 1. It is unclear how induction of MKP-1 is controlled. Here, we report that the transcriptional elongation factors P-TEFb, DSIF and NELF regulate MKP-1 transcription in the pituitary GH4C1 cell line. Prior to stimulation, DSIF, NELF and RNA polymerase II (pol II) associate with the promoter-proximal region of the MKP-1 gene upstream of the elongation block site. Thyrotropin-releasing hormone (TRH) leads to recruitment of P-TEFb along the whole gene and a marked increase of DSIF and pol II downstream of the elongation block site, whereas NELF remains confined to the promoter-proximal region. 5,6-Dichloro-1-ß-D-ribofuranosylbenzimidazole (DRB) an inhibitor of P-TEFb eliminated TRH stimulation of MKP-1 transcription. DRB specifically inhibited TRH-induced recruitment of DSIF and P-TEFb to the MKP-1 gene. Furthermore, DRB treatment eliminated TRH-induced progression along the MKP-1 gene of pol II phosphorylated on Ser-2 of its CTD. These results indicate that P-TEFb is essential for gene-specific stimulated transcriptional elongation in mammalian cells via mechanisms which involve the activation of the DSIF–NELF complex and Ser-2 phosphorylation of pol II.
2 Present address: Centre de Regulació Genòmica, Passeig Marítim, 37-49 E-08003 Barcelona, Spain
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