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NGFI‐B (Nurr77/Nr4a1) orphan nuclear receptor in rat pinealocytes: circadian expression involves an adrenergic‐cyclic AMP mechanism

2004; Wiley; Volume: 91; Issue: 4 Linguagem: Inglês

10.1111/j.1471-4159.2004.02777.x

1471-4159

Ann Humphries, Joan L. Weller, David C. Klein, Rubén Baler, David Carter,

Macrophage Migration Inhibitory Factor

Abstract 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.