TR4 orphan nuclear receptor functions as an apoptosis modulator via regulation of Bcl-2 gene expression

Kim, Eungseok; Lung, Wen; Lin, David L.; Inui, Shigeki; Chen, Yuh Ling; Chang, Chawnshang

doi:10.1016/j.bbrc.2007.06.168

Cited by 20 publications

(12 citation statements)

References 24 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…These findings agree with previous studies that implicated TR4 in regulating cell proliferation and apoptosis, and mice lacking TR4 exhibited significant growth retardation and reduced embryonic and early perinatal survival (25)(26)(27)(28).…”

Section: Discussionsupporting

confidence: 83%

Evidence for orphan nuclear receptor TR4 in the etiology of Cushing disease

Bergsneider

Mirsadraei

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

Cushing disease (CD) is a life-threatening disorder attributed to excess pituitary tumor-derived adrenocorticotrophic hormone (ACTH) and adrenal steroid secretion caused by pituitary tumors. Whereas CD was first described in 1932, the underlying genetic basis driving tumor growth and ACTH secretion remains unsolved. Here, we show that testicular orphan nuclear receptor 4 (TR4, nuclear receptor subfamily 2, group C, member 2) is overexpressed in human corticotroph tumors as well as in human and mouse corticotroph tumor cell lines. Forced overexpression of TR4 in both human and murine tumor cells increased proopiomelanocortin transcription, ACTH secretion, cellular proliferation, and tumor invasion rates in vitro. Conversely, knockdown of TR4 expression reversed all phenotypes. Mechanistically, we show that TR4 transcriptionally activates proopiomelanocortin through binding of a direct repeat 1 response element in the promoter, and that this is enhanced by MAPK-mediated TR4 phosphorylation. In vivo, TR4 overexpression promotes murine corticotroph tumor growth as well as enhances ACTH and corticosterone production, whereas TR4 knockdown decreases circulating ACTH and corticosterone levels in mice harboring ACTH-secreting tumors. Our findings directly link TR4 to the etiology of corticotroph tumors, hormone secretion, and cell growth as well as identify it as a potential target in the treatment of CD.

show abstract

Section: Discussionsupporting

confidence: 83%

Evidence for orphan nuclear receptor TR4 in the etiology of Cushing disease

Bergsneider

Mirsadraei

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

show abstract

“…Interestingly, defective sperm production or spermatogenesis in TR4 (À/À) mice suggests that, like T 3 , TR4 is essential for normal spermatogenesis in mice (Mu et al, 2004). Additionally, TR4 may modulate apoptosis by inducing Bcl-2 gene expression (Kim et al, 2007). Notably, T 3 reportedly regulates apoptosis by retinoic acid in promyeloleukemic HL-60 cells (Hara et al, 2000).…”

Section: Discussionmentioning

confidence: 97%

Human testicular orphan receptor 4 enhances thyroid hormone receptor signaling

Huang

Chen

Liao

et al. 2009

Journal Cellular Physiology

View full text Add to dashboard Cite

The thyroid hormone receptor (TR) and human testicular orphan receptor 4 (TR4) belong to the nuclear hormone receptor superfamily. They are ligand-dependent transcription factors. TR and TR4 bind to a similar thyroid response element (TRE), known as a direct repeat with four nucleotide spacing (DR4). This study examined the possible interaction or cross-talking between those two receptors. We hypothesized that protein-protein interaction between TR4 and TR may promote TR-mediated transcriptional activity. Glutathione S-transferase pull-down and immunoprecipitation assays showed direct interaction between TR and TR4. Electrophoretic mobility-shift assay demonstrated that TR and TR4 could co-occupy the same TRE. The interaction between TR4 and TR may enhance regulation of genes targeted by TR, such as furin, fibrinogen, cdk2 and p21 expression. We found that TR4 function is similar with TR as TR4 alone could regulate expression of some TR target genes, and could increase cell migration or inhibit cell proliferation. Importantly, the TR-dependent inhibition of cell proliferation and stimulation of cell migration are more enhanced in the HepG2-TR cells stably over-expressing TR4. Overall, TR4 not only has modulation abilities similar to TR but also can cross-talk with TR and promote the TR signaling pathway.

show abstract

“…Nr2c2 has been reported to modulate apoptosis [42,43] and its loss in mice is associated with reduced mitochondrial function and increased oxidative stress, and conversely with reduced adipose tissue inflammation, hepatic steatosis and insulin resistance [44-46]. Jazf1-mediated alterations in Nr2c2 could thus affect both insulin sensitivity and β-cell function.…”

Section: Discussionmentioning

confidence: 99%

Diabetes genes identified by genome-wide association studies are regulated in mice by nutritional factors in metabolically relevant tissues and by glucose concentrations in islets

Yoganathan

Chu

et al. 2013

BMC Genet

View full text Add to dashboard Cite

BackgroundGenome-wide association studies (GWAS) have recently identified many new genetic variants associated with the development of type 2 diabetes. Many of these variants are in introns of known genes or between known genes, suggesting they affect the expression of these genes. The regulation of gene expression is often tissue and context dependent, for example occurring in response to dietary changes, hormone levels, or many other factors. Thus, to understand how these new genetic variants associated with diabetes risk may act, it is necessary to understand the regulation of their cognate genes.ResultsWe identified fourteen type 2 diabetes-associated genes discovered by the first waves of GWAS for which there was little prior evidence of their potential role in diabetes (Adam30, Adamts9, Camk1d, Cdc123, Cdkal1, Cdkn2a, Cdkn2b, Ext2, Hhex, Ide, Jazf1, Lgr5, Thada and Tspan8). We examined their expression in metabolically relevant tissues including liver, adipose tissue, brain, and hypothalamus obtained from mice under fasted, non-fasted and high fat diet-fed conditions. In addition, we examined their expression in pancreatic islets from these mice cultured in low and high glucose. We found that the expression of Jazf1 was reduced by high fat feeding in liver, with similar tendencies in adipose tissue and the hypothalamus. Adamts9 expression was decreased in the hypothalamus of high fat fed mice. In contrast, the expression of Camk1d, Ext2, Jazf1 and Lgr5 were increased in the brain of non-fasted animals compared to fasted mice. Most notably, the expression levels of most of the genes were decreased in islets cultured in high glucose.ConclusionsThese data provide insight into the metabolic regulation of these new type 2 diabetes genes that will be important for determining how the GWAS variants affect gene expression and ultimately the development of type 2 diabetes.

show abstract

TR4 orphan nuclear receptor functions as an apoptosis modulator via regulation of Bcl-2 gene expression

Cited by 20 publications

References 24 publications

Evidence for orphan nuclear receptor TR4 in the etiology of Cushing disease

Evidence for orphan nuclear receptor TR4 in the etiology of Cushing disease

Human testicular orphan receptor 4 enhances thyroid hormone receptor signaling

Diabetes genes identified by genome-wide association studies are regulated in mice by nutritional factors in metabolically relevant tissues and by glucose concentrations in islets

Contact Info

Product

Resources

About