Signal-transduction-pathway-specific desensitization of expression of orphan nuclear receptor TIS1

Lim, Robert W.; Yang, Wan-Lin; Yu, Hong

doi:10.1042/bj3080785

Cited by 24 publications

(14 citation statements)

References 30 publications

(31 reference statements)

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“…Adrenergic induction of Nur77 gene expression has been previously demonstrated in the heart (56), in cultured rat astrocytes, and in rat cerebral cortex (1, 2) as well as the mouse C2C12 skeletal muscle cell line (34,35,42), but to our best knowledge has not been reported in brown adipocytes.…”

Section: Discussionmentioning

confidence: 75%

Evidence for Nr4a1 as a cold-induced effector of brown fat thermogenesis

Kanzleiter

Schneider

Walter

et al. 2006

Physiological Genomics

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Section: Discussionmentioning

confidence: 75%

Evidence for Nr4a1 as a cold-induced effector of brown fat thermogenesis

Kanzleiter

Schneider

Walter

et al. 2006

Physiological Genomics

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“…Nur77 is expressed in skeletal muscle (23,24,26,27). Hence, we investigated whether the AB region that encodes the AF-1 domain of Nur77 independently activates gene expression in a cell-specific fashion.…”

Section: The Ab (Af-1) Region Of Nur77 Is Necessary For Agonistindepementioning

confidence: 99%

“…Manner-Nur77 is expressed in skeletal muscle tissue and cells (23,24,26,27). We performed reverse transcription-PCR experiments using total RNA extracted from C2C12 skeletal muscle cells to isolate full-length Nur77 cDNA.…”

Section: Nur77 Trans-activates Gene Expression In a Cell-specificmentioning

confidence: 99%

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

Wansa

Harris

Muscat

2002

Journal of Biological Chemistry

134

116

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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.

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“…We observed a significant (3-to 4-fold) increase in ␤ 2 -AR (ADRB2) expression in the brown adipose tissue from sg/sg mice. Furthermore, adrenergic signaling has been demonstrated to induce the expression of the nuclear receptor subfamily 4, group A (NR4A) subgroup of nuclear receptors that regulate metabolism (18,19,(43)(44)(45). Hence, we examined the expression of these NRs.…”

Section: Decreased Plasma Cholesterol Is Associated With Decreased Exmentioning

confidence: 99%

The Orphan Nuclear Receptor, RORα, Regulates Gene Expression That Controls Lipid Metabolism

Lau¹,

Fitzsimmons²,

Raichur³

et al. 2008

Journal of Biological Chemistry

170

198

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Homozygous staggerer mice (sg/sg) display decreased and dysfunctional retinoic acid receptor-related orphan receptor ␣ (ROR␣) expression. We observed decreases in serum (and liver) triglycerides and total and high density lipoprotein serum cholesterol in sg/sg mice. Moreover, the sg/sg mice were characterized by reduced adiposity (associated with decreased fat pad mass and adipocyte size). Candidate-based expression profiling demonstrated that the dyslipidemia in sg/sg mice is associated with decreased hepatic expression of SREBP-1c, and the reverse cholesterol transporters, ABCA1 and ABCG1. This is consistent with the reduced serum lipids. The molecular mechanism did not involve aberrant expression of LXR and/or ChREBP. However, ChIP and transfection analyses revealed that ROR␣ is recruited to and regulates the activity of the SREBP-1c promoter. Furthermore, the lean phenotype in sg/sg mice is also characterized by significantly increased expression of PGC-1␣, PGC-1␤, and lipin1 mRNA in liver and white and brown adipose tissue from sg/sg mice. In addition, we observed a significant 4-fold increase in ␤ 2 -adrenergic receptor mRNA in brown adipose tissue. Finally, dysfunctional ROR␣ expression protects against diet-induced obesity. Following a 10-week high fat diet, wild-type but not sg/sg mice exhibited a ϳ20% weight gain, increased hepatic triglycerides, and notable white and brown adipose tissue accumulation. In summary, these changes in gene expression (that modulate lipid homeostasis) in metabolic tissues are involved in decreased adiposity and resistance to dietinduced obesity in the sg/sg mice, despite hyperphagia. In conclusion, we suggest this orphan nuclear receptor is a key modulator of fat accumulation and that selective ROR modulators may have utility in the treatment of obesity.The spontaneously arising mouse mutant, staggerer (sg), 4 was initially described and analyzed several decades ago (1).The homozygous mice display ataxia, cerebellar defects, tremor, and imbalance. Subsequently, the gene encoding retinoic acid receptor-related orphan receptor ␣ (ROR␣) (2, 3) was mapped to mouse chromosome 9 in the immediacy of the sg locus (4, 5). ROR␣ is an orphan member of the nuclear receptor superfamily (6). Several studies have identified cholesterol sulfate (and derivatives) as potential ligands for this nuclear receptor (7, 8), however, further studies are required to resolve this issue.The sg mutation has been shown to be an intragenic deletion in the coding region of ROR␣, removing an exon downstream of the DNA binding domain (4,5). This results in a frameshift mutation that affects the co-expressed isoforms ROR␣1 and -␣4 (5). ROR␣ transcript levels are significantly reduced in staggerer (sg/sg) mice, and it has been clearly demonstrated that the sg phenotype is associated with the expression of dysfunctional ROR␣ (9). Moreover, ROR␣-deficient mice display many aspects of the staggerer phenotype (9, 10). Mamontova et al. (11) demonstrated that male and female homozygous staggerer (sg/sg) are charac...

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Signal-transduction-pathway-specific desensitization of expression of orphan nuclear receptor TIS1

Cited by 24 publications

References 30 publications

Evidence for Nr4a1 as a cold-induced effector of brown fat thermogenesis

Evidence for Nr4a1 as a cold-induced effector of brown fat thermogenesis

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

The Orphan Nuclear Receptor, RORα, Regulates Gene Expression That Controls Lipid Metabolism

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