The Activation Function-1 Domain of Nur77/NR4A1 Mediates Trans-activation, Cell Specificity, and Coactivator Recruitment

Abstract

Nur77/NR4A1 is an "orphan member" of the nuclear hormone receptor superfamily. Nur77 and its close relatives Nurr1 and NOR-1 bind as monomers to a consensus binding site, the nerve growth factor induced protein I-B (NGFI-B)-binding response element (NBRE). The Nur77/ NURR1/NOR1 nuclear receptors are classified as immediate early response genes which are induced through multiple signal transduction pathways. They have been implicated in cell proliferation, differentiation, and apoptosis. However, the mechanism of coactivation and ligand independent trans-activation remains unclear. Hence we examined the molecular basis of Nur77-mediated cofactor recruitment and activation. We observed that Nur77 trans-activates gene expression in a cell-specific manner, and operates in an activation function-1 (AF-1)-dependent manner. The AB region encodes an uncommonly potent N-terminal AF-1 domain delimited to between amino acids 50 and 160 and is essential for the ligand-independent activation of gene expression. Steroid receptor coactivator-2 (SRC-2) modulates the activity of the N-terminal AF-1 domain. Moreover, SRC-2 dramatically potentiates the retinoid induced RXR-dependent activation of the Nur77 ligand binding domain (LBD). Interestingly, the N-terminal AB region (not the LBD) facilitates coactivator recruitment and directly interacts with SRC, p300, PCAF, and DRIP-205. Consistent with this, homology modeling indicated that the Nur77 LBD coactivator binding cleft was substantially different from that of retinoic acid receptor ␥, a closely related AF-2-dependent receptor. In particular, the hydrophobic cleft characteristic of nuclear receptors was replaced with a much more hydrophilic surface with a distinct topology. This observation accounts for the inability of this nuclear receptor LBD to directly mediate cofactor recruitment. Furthermore, the AF-1 domain physically associates with the Nur77 C-terminal LBD and synergizes with the retinoid X receptor LBD. Thus, the AF-1 domain plays a major role in Nur77-mediated transcriptional activation, cofactor recruitment, and intra-and intermolecular interactions.

The Transcription Factor NGFI-B (Nur77) and Retinoids Play a Critical Role in Acute Neuroleptic-Induced Extrapyramidal Effect and Striatal Neuropeptide Gene Expression

“…Thus, a ligand-independent transcriptional activity of the NGFI-B/RXR complex that is readily formed after haloperidol-induced NGFI-B mRNA levels in the striatum (Beaudry et al, 2000) may be involved. Indeed, NGFI-B possesses an uncommonly potent activation function-1 (AF-1) domain that is essential for ligand-independent activation of gene expression, cofactor recruitment and interaction with RXR isoforms (Wansa et al, 2002). Thus, we can hypothesize that addition of a RXR agonist (9-cis RA or DHA) modifies the transcriptional activity of the complex (for a ligand-dependent activity) that interferes with haloperidol-induced effects.…”

Cytoplasmic mislocalization of the orphan nuclear receptor Nurr1 is a prognostic factor in bladder cancer

“…[9][10][11] The endogenous signaling molecules that bind to Nurr1 are still unknown. 8 It has been previously shown that Nur77 and Nurr1 are expressed in bladder cancer cell lines. 12 However, the clinical significance in patients has not been reported.…”

“…The nuclear orphan receptors are known to be immediate early response genes induced by a wide range of extracellular signals, including growth factors, apoptotic and inflammatory signals, and hormones, in a cell type-specific manner. 7,8 To our knowledge to date, Nurr1 has mainly been studied as a transcription factor in the nucleus. Mutations in the coding gene have been associated with neurologic diseases, including Parkinson disease, schizophrenia, and manic depression.…”

Prolyl isomerase Pin1 stabilizes and activates orphan nuclear receptor TR3 to promote mitogenesis

“…We thus hypothesized that Pin1-induced TR3 transactivation may be associated with the recruitment of coactivators, such as p300, SRC1, SRC2 and SRC3, all of which were reported to enhance TR3 transactivation activity (Wansa et al, 2002;Maira et al, 2003). The results showed that p300 and the SRCs each promoted TR3 transactivation activity to a moderate degree.…”