Differential regulation of the transcriptional activity of the orphan nuclear receptor NGFI-B by membrane depolarization and nerve growth factor.
The immediate-early gene NGFI-B (also called nur77) encodes an orphan nuclear receptor that activates transcription through a unique response element (NBRE). NGFI-B is rapidly induced and modified via phosphorylation by a variety of stimuli that induce cells to differentiate or to proliferate. We have shown that the in vitro phosphorylation of Ser350 located within the "A-box," a motif necessary for DNA binding by NGFI-B, results in a decrease in the binding of NGFI-B to its response element (Hirata, Y., Kiuchi, K., Chen, H.-C., Milbrandt, J., and Guroff, G. (1993) J. Biol. Chem. 268, 24808-24812). We show here that nerve growth factor (NGF)-induced changes in the in vivo phosphorylation of Ser350 accompany transcriptional deactivation of NGFI-B in PC12 cells, that membrane depolarization and NGF treatment cause differential phosphorylation of NGFI-B, and that the transcriptional activation caused by exogenous expression of NGFI-B or membrane depolarization can be inhibited by NGF treatment. In addition, the mutation of Ser350 to Ala abolished the inhibitory effect of NGF on the transcriptional activation of NGFI-B in PC12 cells. These data could provide new insights into the regulation of transcriptional activity required for some neurons to switch from activity-dependent survival to neurotrophin-dependent survival during development.
Katagiri
Y
Y
Section on Growth Factors, NICHD, National Institutes of Health, Bethesda, Maryland 20892, USA.
Hirata
Y
Y
Milbrandt
J
J
Guroff
G
G
D000818:Animals; D001665:Binding Sites; D004247:DNA / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D004815:Epidermal Growth Factor / Q000494:pharmacology; D016297:Mutagenesis, Site-Directed; D009414:Nerve Growth Factors / Q000378:metabolism*; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1; D016716:PC12 Cells; D010766:Phosphorylation; D011189:Potassium Chloride / Q000378:metabolism; D051381:Rats; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000378:metabolism*; D011987:Receptors, Steroid / Q000235:genetics / Q000378:metabolism*; D011994:Recombinant Proteins / Q000378:metabolism; D012694:Serine / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D015533:Transcriptional Activation
D004268:DNA-Binding Proteins; D009414:Nerve Growth Factors; C539820:Nr4a1 protein, rat; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1; D018160:Receptors, Cytoplasmic and Nuclear; D011987:Receptors, Steroid; D011994:Recombinant Proteins; D014157:Transcription Factors; D012694:Serine; D004815:Epidermal Growth Factor; D011189:Potassium Chloride; D004247:DNA