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.
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.
Fujita
Toshitsugu
T
Fondation pour Recherches Médicales, 64 av. de la Roseraie, University of Geneva, 1211 Geneva, Switzerland.
Ryser
Stephan
S
Piuz
Isabelle
I
Schlegel
Werner
W
D000818:Animals; D018929:Cell Culture Techniques; D002478:Cells, Cultured; D047369:Chromatin Immunoprecipitation; D016895:Culture Media, Serum-Free; D042863:Cyclin-Dependent Kinase 9 / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D017781:Genes, Immediate-Early; D008954:Models, Biological; D010766:Phosphorylation / Q000187:drug effects; D010902:Pituitary Gland / Q000166:cytology; D042925:Positive Transcriptional Elongation Factor B / Q000378:metabolism*; D011233:Precipitin Tests; D051381:Rats; D015398:Signal Transduction; D013973:Thyrotropin-Releasing Hormone / Q000494:pharmacology; D013997:Time Factors; D014158:Transcription, Genetic; D015854:Up-Regulation
D016895:Culture Media, Serum-Free; D013973:Thyrotropin-Releasing Hormone; D042925:Positive Transcriptional Elongation Factor B; D042863:Cyclin-Dependent Kinase 9; D048049:Extracellular Signal-Regulated MAP Kinases