NGFI-B (Nurr77/Nr4a1) orphan nuclear receptor in rat pinealocytes: circadian expression involves an adrenergic-cyclic AMP mechanism.
NGFI-B (Nur77/Nr4a1) is a member of a nuclear steroid receptor subgroup that includes the related factors Nurr1 (Nr4a2) and NOR-1 (Nr4a3). These proteins do not have recognized ligands and in fact function independently as orphan receptors with transcriptional regulatory activity. In the present study, expression of the NGFI-B gene in the rat pineal gland was found to exhibit a robust circadian rhythm, with elevated levels of NGFI-B mRNA occurring at night. The rhythm of NGFI-B mRNA is translated into a circadian rhythm of NGFI-B protein, which accumulates in the nucleus of pinealocytes. In addition, there is a parallel marked nocturnal increase in pineal DNA binding activity to a NGFI-B response element (NBRE, AAAGGTCA). Pharmacological studies indicate that NGFI-B mRNA and protein levels are elevated via activation of adrenergic receptors. NGFI-B protein levels are also elevated by dibutyryl cyclic AMP, as in other systems. In the pineal gland, regulation of NGFI-B expression also involves the AP-1 protein Fra-2, based on studies with a transgenic Fra-2 knockdown rat, in which pineal NGFI-B expression increases. This set of observations extends the number of pineal genes that are known to be regulated by Fra-2, and also provides the first indication that a member of the NGFI-B group of nuclear receptors is involved in controlling gene expression in the pineal gland.
Humphries
Ann
A
School of Biosciences, Cardiff University, Cardiff, UK.
Weller
Joan
J
Klein
David
D
Baler
Ruben
R
Carter
David A
DA
D000818:Animals; D030801:Animals, Genetically Modified; D003994:Bucladesine / Q000494:pharmacology; D002467:Cell Nucleus / Q000378:metabolism; D002940:Circadian Rhythm / Q000502:physiology*; D000242:Cyclic AMP / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D024202:Electrophoretic Mobility Shift Assay; D051921:Fos-Related Antigen-2; D005786:Gene Expression Regulation / Q000235:genetics / Q000502:physiology; D005799:Genes, Dominant; D008297:Male; D009638:Norepinephrine / Q000494:pharmacology; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1; D009924:Organ Culture Techniques; D010870:Pineal Gland / Q000737:chemistry* / Q000187:drug effects / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D011941:Receptors, Adrenergic / Q000187:drug effects / Q000378:metabolism*; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000378:metabolism*; D011987:Receptors, Steroid / Q000235:genetics / Q000378:metabolism*; D020218:Response Elements / Q000235:genetics / Q000502:physiology; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*
D004268:DNA-Binding Proteins; D051921:Fos-Related Antigen-2; C497874:Fosl2 protein, rat; C539820:Nr4a1 protein, rat; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1; D012333:RNA, Messenger; D011941:Receptors, Adrenergic; D018160:Receptors, Cytoplasmic and Nuclear; D011987:Receptors, Steroid; D014157:Transcription Factors; D003994:Bucladesine; D000242:Cyclic AMP; D009638:Norepinephrine