• Animal cells and systems
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• 제2권4호
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• pp.489-493
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• 1998

Various heterodimers of the thyroid hormone receptor (TR) with other nuclear hormone receptors confer a wide range of transcriptional activities on thyroid hormone response elements (TREs) in the presence of the thyroid hormone ($T_3$). The present study analyzed the potential roles of retinoid X receptor (RXR) isoforms $\alpha$ and $\beta$ in $T_3$-mediated transcription on a well characterized TRE, a direct repeat of AGGTCA separated by four nucleo-tides (DR4), using electrophoretic mobility shift assays and transient transfection in CV-1 cells. We demonstrated that RXR$\alpha$ supressed liganded $TR_{\alpha}$-induced transcription while $RXR_{\beta}$ did not although both $TR_{\alpha}/RXR_{\alpha}$ and $TR_{\alpha}/RXR_{\beta}$ heterodimers were the predominant forms bound to the TRE-DR4 in the presence of $T_3$. We further demonstrated using Scatchard analysis that the two heterodimers had similar affinities for the TRE-DR4. All these observations suggest that the TRE-DR4 accomodates different types of TR/RXR heterodimers for a more finely tuned transcriptional response to $T_3$.

• 한국식품위생안전성학회지
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• 제21권3호
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• pp.171-180
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• 2006

Peroxisome proliferator-activated receptor-gamma$(PPAR{\gamma})$ 는 DNA와 결합하기 위해 retinoid-X receptor(RXR)와 heterodimer를 형성해야만 한다. 그리고 전사에 대한 최대활성은 수용체에 대한 리간드 특이성에 의하는 것으로 생각되고 있다. 활성화된 $(PPAR{\gamma})$ 와 $(PPAR{\gamma})$ 리간드는 종양억제 PTEN의 조절을 통해 종양세포의 성장에 영향을 끼치게 된다. 본 연구의 목적은 $(PPAR{\gamma})$ ligand, ciglitazone그리고 RXR ligand로 동시에 자극하였을 때 급성전골수성백혈병(APL) 세포에 대해 이들이 함께 PTEN upregulate를 조절할 수 있는지를 결정하기 위함이다. 그리고 이들 세포의 성장과 분화주기에 대해 강력한 억제 능이 있는지를 결정하고자 하였다. 즉, 사람의 백혈병세포주인 HL-60세포에 all-trans-retinol과 ciglutazone을 노출시킨 뒤 PTEN 발현에 대한 측정을 위해 RT-PCR법으로 PTEN mRNA 발현 정도를 확인하고 western blot으로 분석하였다 세포주기의 분석은 propidium iodide(PI) 염색법과 FACScan으로 분석하였고, HL-60 cells에서 $(PPAR{\gamma})$ ligand, ciglitazone, 그리고 RXR ligand, retinoic acid 그리고 upregulated PTEN 발현에 대한 time- and dose-dependent방법으로 각각 확인하였던 바 ciglitazone과 retinoic acid를 동시 조합하여 처치하였을 때 유의적인 효과를 인정할 수 있었다. 더욱이 이들 혼합 물질은 세포의 성장과 G, phase를 동시 억제하는 능력이 있었다. 그러므로 $(PPAR{\gamma})$의 활성에 있어 RXR heterodimer가 사람의 백혈병세포에 대한 조절 경로로서 존재하며, PTEN의 upregulation을 통해 백혈병을 조절하기 때문에 백혈병의 예방 및 치료 접근에 $(PPAR{\gamma})$와 RXR ligands가 중요한 역할을 할 것이다.

• Molecules and Cells
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• 제38권4호
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• pp.356-361
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• 2015

Mitochondrial dysfunction is associated with insulin resistance and diabetes. We previously showed that retinoid X receptor ${\alpha}$ ($RXR{\alpha}$) played an important role in transcriptional regulation of oxidative phosphorylation (OXPHOS) genes in cells with mitochondrial dysfunction caused by mitochondrial DNA mutation. In this study, we investigated whether mitochondrial dysfunction induced by incubation with OXPHOS inhibitors affects insulin receptor substrate 1 (IRS1) mRNA and protein levels and whether $RXR{\alpha}$ activation or overexpression can restore IRS1 expression. Both IRS1 and $RXR{\alpha}$ protein levels were significantly reduced when C2C12 myotubes were treated with the OXPHOS complex inhibitors, rotenone and antimycin A. The addition of $RXR{\alpha}$ agonists, 9-cis retinoic acid (9cRA) and LG1506, increased IRS1 transcription and protein levels and restored mitochondrial function, which ultimately improved insulin signaling. $RXR{\alpha}$ overexpression also increased IRS1 transcription and mitochondrial function. Because $RXR{\alpha}$ overexpression, knock-down, or activation by LG1506 regulated IRS1 transcription mostly independently of mitochondrial function, it is likely that $RXR{\alpha}$ directly regulates IRS1 transcription. Consistent with the hypothesis, we showed that $RXR{\alpha}$ bound to the IRS1 promoter as a heterodimer with peroxisome proliferator-activated receptor ${\delta}$ ($PPAR{\delta}$). These results suggest that $RXR{\alpha}$ overexpression or activation alleviates insulin resistance by increasing IRS1 expression.

• 대한약리학회:학술대회논문집
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• 대한약리학회 2006년도 58th Annual Meeting of The Korean Society of Pharmacology
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• pp.68.2-68.2
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• 2006

• Molecular & Cellular Toxicology
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• 제3권1호
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• pp.1-10
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• 2007

The persistent and ubiquitous environmental contaminant, tributyltin chloride (TBT), induces not only imposex in gastropods but also the differentiation of adipocytes in vitro and increases adipose mass in vivo in vertebrates. TBT is a nanomolar affinity ligand for retinoid X receptor (RXR) in the rock shell(Thais clavigera) and for both the RXR and the peroxisome proliferator activated receptor $\gamma(PPAR\gamma)$ in the amphibian (Xenopus laevis), mouse, and human. The molecular mechanisms underlying induction of imposex by TBT have not been clarified, though several hypotheses are proposed. TBT promotes adipogenesis in the murine 3T3-L1 cell model and perturbs key regulators of adipogenesis and lipogenic pathways in vivo primarily through activation of RXR and $PPAR\gamma$. Moreover, in utero exposure to TBT leads to strikingly elevated lipid accumulation in adipose depots, liver, and testis of neonate mice and results in increased adipose mass in adults. In X. laevis, ectopic adipocytes form in and around gonadal tissues following organotin, RXR or $PPAR\gamma$ ligand exposure. TBT represents the first example of an environmental endocrine disrupter that promotes adverse effects from gastropods to mammals.

• The Korean Journal of Physiology and Pharmacology
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• 제25권5호
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• pp.385-393
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• 2021

Tissue factor (TF) activates the coagulation system and has an important role in the pathogenesis of various diseases. Our previous study stated that retinoid receptors (RAR-α and RXR-α) are released as a lipid droplet in monocrotaline/lipopolysaccharide-induced idiosyncratic liver toxicity in mice. Herein, the interdependence between the release of retinoid receptors RAR-α and RXR-α and TF in N-acetyl-p-aminophenol (APAP)-induced mice liver toxicity, is investigated. Serum alanine transaminase (ALT) level, platelet and white blood cells (WBCs) counts, protein expression of fibrin, TF, cyclin D1 and cleaved caspase-3 in liver tissues are analyzed. In addition, histopathological evaluation and survival study are also performed. The results indicate that using of TF-antisense (TF-AS) deoxyoligonucleotide (ODN) injection (6 mg/kg), to block TF protein synthesis, significantly restores the elevated level of ALT and WBCs and corrects thrombocytopenia in mice injected with APAP. TF-AS prevents the peri-central overexpression of liver TF, fibrin, cyclin D1 and cleaved caspase-3. The release of RXR-α and RAR-α droplets, in APAP treated sections, is inhibited upon treatment with TF-AS. In conclusion, the above findings designate that the released RXR-α and RAR-α in APAP liver toxicity is TF dependent. Additionally, the enhancement of cyclin D1 to caspase-3-dependent apoptosis can be prevented by blocking of TF protein synthesis.

• 한국독성학회:학술대회논문집
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• 한국독성학회 2005년도 춘계 국제심포지엄 및 학술대회
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• pp.151-151
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• 2005

• 한국응용약물학회:학술대회논문집
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• 한국응용약물학회 2003년도 Annual Meeting of KSAP : International Symposium on Pharmaceutical and Biomedical Sciences on Obesity
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• pp.89-89
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• 2003

Exposure of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) causes a variety of biological and toxicology effects, most of which are mediated by aryl hydrocarbon receptor (AhR). The ligand-bound AhR as a heterodimer with AhR nuclear translocator (ARNT) binds to its specific DNA recognition site, the dioxin-responsive element (DRE), and it results in increased transcription of CYP1A1 gene. Retinoic acid (RA) regulates the transcription of various genes for several essential functions through binding to two classes of nuclear receptors, the retinoic acid receptor (RAR) and retinoid X receptor (RXR). Constitutive androstane receptor (CAR) also regulates the transcription of gene. In this study, we have examined how RAR, RXR and CAR regulated CYP1A1 in rainbow trout hepatoma cell (RTH 149) using luciferase reporter gene assay system. We did transient transfection with CYP1A1 luciferase reporter gene and treated with TCDD, all-trans RA, 9-cis RA and phenobarbital. Treatment of all-trans RA, 9-cis RA or phenobarbital decreased the TCDD induced transcription of CYP1Al. When we did transient cotransfection with CYP1A1 luciferase reporter gene and RXR, as increase of RXR concentration, the TCDD induced transcription of CYP1A1 was decreased. Transfection with CAR also decreased the TCDD induced transcription of CYP1A1 in RTH 149 cells.

• Asian Pacific Journal of Cancer Prevention
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• 제15권24호
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• pp.10819-10824
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• 2015

Aims: To explore the effect and probable mechanism of a synthetic retinoid 4-amino-2-tri-fluoromethylphenyl ester (ATPR) on apoptosis of MDA-MB-231 breast cancer cells. Materials and Methods: MTT assays were performed to measure the proliferation of MDA-MB-231 cells treated with different concentrations of all-trans retinoic acid (ATRA) and ATPR. Morphologic changes were observed by microscopy. The apoptosis rates and cell cycling of MDA-MB-231 cells treated with ATRA or ATPR were assessed using flow cytometry analysis. Expression of retinoic acid receptor and phosphorylation of ERK, JNK, p38 proteins were detected by Western blotting. Results: Treatment of the cells with the addition of $15{\mu}mol/L$ ATPR for 48 h clearly demonstrated reduced cell numbers and deformed cells, whereas no changes in the number and morphology were observed after treatment with ATRA. The apoptosis rate was 33.2% after breast cancer MDA-MB-231 cells were treated by ATPR ($15{\mu}mol/L$) whereas ATRA ($15{\mu}mol/L$) had no apoptotic effect. ATPR inhibited the phosphorylation of ERK, JNK, and p38 while ATRA had no significant effect. ATPR inhibited the expression of BiP and increased the expression of Chop at the protein level compared with control groups, ATRA and ATPR both decreased the protein expression of $RXR{\alpha}$, ATPR reduced the protein expression of $RAR{\beta}$ and $RXR{\beta}$ while ATRA did not decrease $RAR{\beta}$ or $RXR{\beta}$. Conclusions: ATPR could induce apoptosis of breast cancer MDA-MB-231 cells, possible mechanisms being binding to $RAR{\beta}/RXR{\beta}$ heterodimers, then activation of ER stress involving the MAPK pathway.

• 한국환경독성학회:학술대회논문집
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• 한국환경독성학회 2003년도 추계국제학술대회
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• pp.179-179
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• 2003

Exposure of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) causes a variety of biological and toxicology effects, most of which are mediated by aryl hydrocarbon receptor (AhR). The ligand-bound AhR as a heterodimer with AhR nuclear translocator (ARNT) binds to its specific DNA recognition site, the dioxin-responsive element (DRE), and it results in increased transcription of CYP1A1 gene. Retinoic acid (RA) regulates the transcription of various genes for several essential functions through binding to two classes of nuclear receptors, the retinoic acid receptor (RAR) and retinoid X receptor (RXR). Constitutive androstane receptor (CAR) also regulates the transcription of gene. In this study, we have examined how RAR, RXR and CAR regulated CYP1A1 in rainbow trout hepatoma cell (RTH 149) using luciferase reporter gene assay system. We did transient transfection with CYP1A1 luciferase reporter gene and treated with TCDD, all-trans RA, 9-cis RA and phenobarbital. Treatment of all-trans RA, 9-cis RA or phenobarbital decreased the TCDD induced transcription of CYP1A1. When we did transient cotransfection with CYP1A1 luciferase reporter gene and RXR, as increase of RXR concentration, the TCDD induced transcription of CYP1A1 was decreased. Transfection with CAR also decreased the TCDD induced transcription of CYP1A1 in RTH 149 cells.