Neurokinin-B transcription in erythroid cells: direct activation by the hematopoietic transcription factor GATA-1.
The GATA family of transcription factors establishes genetic networks that control developmental processes including hematopoiesis, vasculogenesis, and cardiogenesis. We found that GATA-1 strongly activates transcription of the Tac-2 gene, which encodes proneurokinin-B, a precursor of neurokinin-B (NK-B). Neurokinins function through G protein-coupled transmembrane receptors to mediate diverse physiological responses including pain perception and the control of vascular tone. Whereas an elevated level of NK-B was implicated in pregnancy-associated pre-eclampsia (Page, N. M., Woods, R. J., Gardiner, S. M., Lomthaisong, K., Gladwell, R. T., Butlin, D. J., Manyonda, I. T., and Lowry, P. J. (2000) Nature 405, 797-800), the regulation of NK-B synthesis and function are poorly understood. Tac-2 was expressed in normal murine erythroid cells and was induced upon ex vivo erythropoiesis. An estrogen receptor fusion to GATA-1 (ER-GATA-1) and endogenous GATA-1 both occupied a region of Tac-2 intron-7, which contains two conserved GATA motifs. Genetic complementation analysis in GATA-1-null G1E cells revealed that endogenous GATA-2 occupied the same region of intron-7, and expression of ER-GATA-1 displaced GATA-2 and activated Tac-2 transcription. Erythroid cells did not express neurokinin receptors, whereas aortic and yolk sac endothelial cells differentially expressed neurokinin receptor subtypes. Since NK-B induced cAMP accumulation in yolk sac endothelial cells, these results suggest a new mode of vascular regulation in which GATA-1 controls NK-B synthesis in erythroid cells.
Pal
Saumen
S
University of Wisconsin Medical School, Molecular and Cellular Pharmacology Program, Department of Pharmacology, Madison, Wisconsin 53706, USA.
Nemeth
Michael J
MJ
Bodine
David
D
Miller
Jeffery L
JL
Svaren
John
J
Thein
Swee Lay
SL
Lowry
Philip J
PJ
Bresnick
Emery H
EH
D000818:Animals; D001483:Base Sequence; D002460:Cell Line; D017931:DNA Primers / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism*; D041905:Erythroid Cells / Q000378:metabolism*; D050981:Erythroid-Specific DNA-Binding Factors; D005260:Female; D050982:GATA1 Transcription Factor; D006801:Humans; D066298:In Vitro Techniques; D051379:Mice; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D015287:Neurokinin B / Q000235:genetics*; D020411:Oligonucleotide Array Sequence Analysis; D011498:Protein Precursors / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015320:Tachykinins / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism*; D015533:Transcriptional Activation
D017931:DNA Primers; D004268:DNA-Binding Proteins; D050981:Erythroid-Specific DNA-Binding Factors; D050982:GATA1 Transcription Factor; C494688:GATA1 protein, human; C494689:Gata1 protein, mouse; D011498:Protein Precursors; D012333:RNA, Messenger; D015320:Tachykinins; D014157:Transcription Factors; C044206:preprotachykinin; D015287:Neurokinin B