Up-regulation of tyrosine hydroxylase gene transcription by tetradecanoylphorbol acetate is mediated by the transcription factors Ets-like protein-1 (Elk-1) and Egr-1.
Tyrosine hydroxylase is the rate-limiting enzyme in the biosynthesis of catecholamines. Expression of the tyrosine hydroxylase gene is regulated at the transcriptional level by extracellular signalling molecules, including epidermal growth factor (EGF), nerve growth factor (NGF) and glucocorticoids. We have analysed the stimulation of tyrosine hydroxylase gene transcription by the phorbol ester 12-O-tetradecanoylphorbol-13-acetate (TPA) in noradrenergic locus coeruleus-like CATH.a cells and observed a striking enhancement of the transcriptional activation potential of the ternary complex factor Ets-like protein-1 (Elk-1), a key transcriptional regulator of serum response element-driven gene transcription. Likewise, TPA strongly up-regulated the biosynthesis of the transcription factor Egr-1 via distal serum response elements within the Egr-1 5'-flanking region. Subsequently, enhancement of the transcriptional activation potential of Egr-1 was observed. Overexpression of Egr-1 was sufficient to activate transcription of a tyrosine hydroxylase promoter/reporter gene, corroborating the view that the tyrosine hydroxylase gene is a target gene of Egr-1. Expression of dominant-negative mutants of Elk-1 or Egr-1 impaired TPA-induced stimulation of a tyrosine hydroxylase promoter/reporter gene transcription. In contrast, dominant-negative mutants of the transcription factors activating transcription factor (ATF)-2, ATF4, cAMP response element-binding protein, c-Jun and CCAAT/enhancer binding protein (C/EBP) did not change TPA-induced tyrosine hydroxylase promoter activity, indicating that these proteins are not part of the TPA-mediated signalling cascade directed towards the tyrosine hydroxylase gene.
Stefano
Luisa
L
Department of Medical Biochemistry and Molecular Biology, University of Saarland Medical Center, Homburg, Germany.
Al Sarraj
Jude
J
Rössler
Oliver G
OG
Vinson
Charles
C
Thiel
Gerald
G
D000818:Animals; D002273:Carcinogens / Q000494:pharmacology; D002395:Catecholamines / Q000096:biosynthesis*; D002460:Cell Line; D051766:Early Growth Response Protein 1 / Q000187:drug effects / Q000378:metabolism*; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects / Q000502:physiology; D017930:Genes, Reporter / Q000187:drug effects / Q000502:physiology; D008125:Locus Coeruleus / Q000201:enzymology; D051379:Mice; D009474:Neurons / Q000187:drug effects / Q000201:enzymology*; D011401:Promoter Regions, Genetic / Q000187:drug effects / Q000502:physiology; D050436:Regulatory Elements, Transcriptional / Q000187:drug effects / Q000502:physiology; D027602:Serum Response Element / Q000187:drug effects / Q000502:physiology; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014157:Transcription Factors / Q000187:drug effects / Q000378:metabolism; D015533:Transcriptional Activation / Q000187:drug effects / Q000502:physiology*; D014446:Tyrosine 3-Monooxygenase / Q000096:biosynthesis* / Q000235:genetics; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology; D050807:ets-Domain Protein Elk-1 / Q000187:drug effects / Q000378:metabolism*
D002273:Carcinogens; D002395:Catecholamines; D051766:Early Growth Response Protein 1; C486109:Egr1 protein, mouse; D014157:Transcription Factors; D050807:ets-Domain Protein Elk-1; D014446:Tyrosine 3-Monooxygenase; D013755:Tetradecanoylphorbol Acetate