GATA-3 regulates the transcriptional activity of tyrosine hydroxylase by interacting with CREB.
The zinc finger transcription factor GATA-3 is a master regulator of type 2 T-helper cell development. Interestingly, in GATA-3-/- mice, noradrenaline (NA) deficiency is a proximal cause of embryonic lethality. However, neither the role of GATA-3 nor its target gene(s) in the nervous system were known. Here, we report that forced expression of GATA-3 resulted in an increased number of tyrosine hydroxylase (TH) expressing neurons in primary neural crest stem cell (NCSC) culture. We also found that GATA-3 transactivates the promoter function of TH via specific upstream sequences, a domain of the TH promoter residing at -61 to -39 bp. Surprisingly, this domain does not contain GATA-3 binding sites but possesses a binding motif, a cAMP response element (CRE), for the transcription factor, CREB. In addition, we found that site-directed mutation of this CRE almost completely abolished transactivation of the TH promoter by GATA-3. Furthermore, protein-protein interaction assays showed that GATA-3 is able to physically interact with CREB in vitro as well as in vivo. Based on these results, we propose that GATA-3 may regulate TH gene transcription via a novel and distinct protein-protein interaction, and directly contributes to NA phenotype specification.
Hong
Seok Jong
SJ
Molecular Neurobiology Laboratory, McLean Hospital, Harvard Medical School, Belmont, Massachusetts 02478, USA.
Huh
Youngbuhm
Y
Chae
Han
H
Hong
Sunghoi
S
Lardaro
Thomas
T
Kim
Kwang-Soo
KS
D000818:Animals; D001665:Binding Sites / Q000235:genetics; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D002642:Chick Embryo; D003370:Coturnix; D017362:Cyclic AMP Response Element-Binding Protein / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology; D050990:GATA3 Transcription Factor / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D015971:Gene Expression Regulation, Enzymologic / Q000502:physiology*; D006367:HeLa Cells; D006801:Humans; D051381:Rats; D015533:Transcriptional Activation / Q000502:physiology*; D014446:Tyrosine 3-Monooxygenase / Q000235:genetics* / Q000378:metabolism*
D017362:Cyclic AMP Response Element-Binding Protein; D050990:GATA3 Transcription Factor; C494749:GATA3 protein, human; D014446:Tyrosine 3-Monooxygenase