Dimer-Specific Potentiation of NGFI-B (Nur77) Transcriptional Activity by the Protein Kinase A Pathway and AF-1-Dependent Coactivator Recruitment

Abstract

The NGFI-B (Nur77) subfamily of orphan nuclear receptors (NRs), which also includes Nurr1 and NOR1, bind the NurRE regulatory element as either homo-or heterodimers formed between subfamily members. These NRs mediate the activation of pituitary proopiomelanocortin (POMC) gene transcription by the hypothalamic hormone corticotropin-releasing hormone (CRH), an important link between neuronal and endocrine components of the hypothalamo-pituitary-adrenal axis. CRH effects on POMC transcription do not require de novo protein synthesis. We now show that CRH signals activate Nur factors through the cyclic AMP/protein kinase A (PKA) pathway. CRH and PKA rapidly increase nuclear DNA binding activity of NGFI-B dimers but not monomers. Accordingly, CRH-or PKA-activated Nur factors enhance dimer (but not monomer) target response elements. We also show that p160/SRC coactivators are recruited to Nur dimers (but not to monomers) and that coactivator recruitment to the NurRE is enhanced in response to CRH. Moreover, PKA-and coactivator-induced potentiation of NGFI-B activity are primarily exerted through the N-terminal AF-1 domain of NGFI-B. The TIF2 (SRC-2) glutamine-rich domain is required for this activity. Taken together, these results indicate that Nur factors behave as endpoint effectors of the PKA signaling pathway acting through dimers and AF-1-dependent recruitment of coactivators.

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

“…Since activation of the dopamine D 2 receptor normally reduces cAMP levels and striatal levels of NGFI-B (Gervais et al, 1999), blockade of the D 2 receptor by neuroleptics may increase or release inhibition of cAMP-dependent protein kinase activity (PKA) and result in an upregulation NGFI-B expression (Beaudry et al, 2000). Also, we cannot exclude that posttranslational modification (phosphorylation), which greatly affect NGFI-B activity (Maira et al, 2003), of pre-existing NGFI-B or de novo haloperidol-induced NGFI-B may play a role in the effects observed here. Other signaling pathways such as those implicating phospholipase C, intracellular calcium stores and protein kinase C (PKC) might also be involved (see Hernandez-Lopez et al, 2000).…”

“…We have previously shown that acute haloperidol strongly increased NGFI-B mRNA levels in the rat forebrain (Beaudry et al, 2000), but the intracellular signaling events triggering by neuroleptics and leading to modulation of NGFI-B are unknown. It has been shown in vitro that NGFI-B is a direct target of kinases associated with G proteincoupled receptors intracellular signaling such as cyclic AMP (cAMP) and MAPK pathways (Kovalovsky et al, 2002;Slagsvold et al, 2002;Maira et al, 2003). Since activation of the dopamine D 2 receptor normally reduces cAMP levels and striatal levels of NGFI-B (Gervais et al, 1999), blockade of the D 2 receptor by neuroleptics may increase or release inhibition of cAMP-dependent protein kinase activity (PKA) and result in an upregulation NGFI-B expression (Beaudry et al, 2000).…”

Evidence‐Based Theory for Integrated Genome Regulation of Ontogeny—An Unprecedented Role of Nuclear FGFR1 Signaling

“…Additionally, RXR is highly versatile with respect to its heterodimerization; among the many other nuclear receptors with which it can interact are two members of the orphan nuclear subfamily, Nur77 and Nurr1. These factors also function independently by binding Nur‐response elements, as monomers (NBRE) and dimers (NurRE) (Maira et al, 1999; Maira et al, 2003; Lefebvre et al, 2010). nFGFR1 forms CBP‐containing low mobility chromatin complexes with RXR, RAR, and Nurs.…”

Involvement of Nurr-1/Nur77 in corticotropin-releasing factor/urocortin1-induced tyrosinase-related protein 1 gene transcription in human melanoma HMV-II cells

“…In fact, in this study, TRP1 promoter activity was strongly stimulated by both Nurr-1 and Nur77. Although the induction of Nurr-1/Nur77 expression was not so strong, it has been reported that CRF not only induces Nurr-1/Nur77 but also modulates dephosphorylation of the proteins (Maira et al, 2003). Therefore, the effects of Nurr-1/Nur77 on TRP1 gene expression levels may also be affected by the qualitative level through, for example, dephosphorylation of Nurr-1/Nur77.…”