Menin represses JunD transcriptional activity in protein kinase Cθ-mediated Nur77 expression

Kim, Hyungsoo; Lee, Ji Eun; Kim, Bu Yeon; Cho, Eun Jung; Kim, Seong-Tae; Youn, Hong Duk

doi:10.1038/emm.2005.57

Cited by 37 publications

(27 citation statements)

References 37 publications

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“…Inhibition of the MAPK/MEK1/2 pathway by a specific inhibitor (U0126) significantly attenuated the 5-HT-induced Nur77 expression, demonstrating a direct link between MEK1/2 activation and 5-HT-induced Nur77 expression in PASMCs. Depending on the cell type, several transcription factors, including CREB, AP-1, MEF-2, and NF-kB, have been previously implicated in the expression of NR4A family (36)(37)(38)(39). In vascular cells, CREB, however, appears to be a key factor for the induction of NR4A receptor.…”

Section: Discussionmentioning

confidence: 99%

Nur77 Suppresses Pulmonary Artery Smooth Muscle Cell Proliferation through Inhibition of the STAT3/Pim-1/NFAT Pathway

Liu

Zhang

et al. 2014

Am J Respir Cell Mol Biol

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The orphan nuclear receptor 4A (NR4A) family plays critical roles in the regulation of cell proliferation, differentiation, and survival in the cardiovascular system. However, the molecular mechanisms underlying the regulation of NR4A receptor expression and its role in pulmonary artery smooth muscle cell (PASMC) function remain unclear. Here, we investigated whether the NR4A family regulates PASMC proliferation, and if so, which mechanisms are involved. By using quantitative real-time RT-PCR, we showed that the orphan nuclear receptor Nur77 was the most abundant member of NR4A family expressed in rat PASMCs, as compared with the two other members, NOR-1 and Nurr1. In rat PASMCs, expression of Nur77 was robustly induced in response to several pathologic stimuli of pulmonary arterial hypertension (PAH), such as hypoxia, 5-hydroxytryptamine (5-HT), platelet-derived growth factor, and endothelin-1. Importantly, Nur77 was also significantly increased in lungs of rats with monocrotaline-induced PAH. Furthermore, we demonstrated that 5-HT markedly up-regulated Nur77 expression through the mitogen-activated protein kinases/extracellular signal-regulated kinase 1/2 pathway. Overexpression of Nur77 inhibited 5-HT-induced PASMC proliferation, as well as the expression of cyclin D1 and proliferating cell nuclear antigen. Mechanistically, we demonstrated that Nur77 specifically interacts with signal transducer and activator of transcription 3, thus inhibiting its phosphorylation and expression of its target genes, such as Pim-1, nuclear factor of activated T cells c2, and survivin in PASMCs. These results indicate that Nur77 is a novel negativefeedback regulator of PASMC proliferation through inhibition of the signal transducer and activator of transcription 3/Pim-1/nuclear factor of activated T cells axis. Modulation of Nur77 activity may potentially represent a novel therapeutic strategy for the treatment of PAH.Keywords: orphan nuclear receptor Nur77; pulmonary artery hypertension; smooth muscle cells; proliferation; signal transducer and activator of transcription 3 Clinical RelevanceUsing in vitro and in vivo models of pulmonary arterial hypertension (PAH), we demonstrated that the orphan nuclear receptor, Nur77, is substantially increased in proliferative pulmonary artery smooth muscle cells (PASMCs) and the lungs of rats with experimental PAH. Overexpression of Nur77 markedly inhibited 5-hydroxytryptamine-induced PASMC proliferation, phosphorylation of signal transducer and activator of transcription 3, and expression of Pim-1, nuclear factor of activated T cells c2, and survivin. These results implicate critical roles of Nur77 in suppressing PASMC proliferation and the development of experimental PAH.

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Section: Discussionmentioning

confidence: 99%

Nur77 Suppresses Pulmonary Artery Smooth Muscle Cell Proliferation through Inhibition of the STAT3/Pim-1/NFAT Pathway

Liu

Zhang

et al. 2014

Am J Respir Cell Mol Biol

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“…Initially, Nur77 was identified as an immediate-early gene that is responsive to various growth factors related to cell proliferation (Hazel et al, 1988;Williams and Lau, 1993;Yoon and Lau, 1994;Kolluri et al, 2003;Kim et al, 2005b). Nur77 was also found to play a critical function in T cell and cancer cell apoptosis (Li et al, 2000;Winoto and Littman, 2002;Lin et al, 2004).…”

Section: Discussionmentioning

confidence: 99%

“…After 24 h of incubation, cells were treated with MG132 for 5 h. Each cell lysates was immunoprecipitated with anti-HIF-1α polyclonal antibody and probed with anti-ubiquitin anti- HEK293 cells were transfected with pCS2+MT-Nur77. After 24 h of incubation, nuclear extracts were prepared as described previously (Kim et al, 2005b). Nuclear extracts were subjected to SDS-PAGE, and then immunoblotted with HIF-1α antibody or anti-lamin B antibody.…”

Section: Nur77 Inhibits the Pvhl-mediated Degradation Of Hif-1αmentioning

confidence: 99%

Nur77 upregulates HIF-α by inhibiting pVHL-mediated degradation

Kim

Cho

et al. 2008

Exp Mol Med

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In this study, we investigated the role of Nur77, an orphan nuclear receptor, in HIF-α transcriptional activity. We found that Nur77 associates and stabilizes HIF-1α via indirect interaction. Nur77 was found to interact with pVHL in vivo via the α-domain of pVHL. By binding to pVHL, Nur77 competed with elongin C for pVHL binding. Moreover, Nur77-binding to pVHL inhibited the pVHL-mediated ubiquitination of HIF-1α and ultimately increased the stability and transcriptional activity of HIF-1α. The ligand-binding domain of Nur77 was found to interact with pVHL and the expression of this ligand-binding domain was sufficient to stabilize and transactivate HIF-1α. Under the conditions that cobalt chloride was treated or pVHL was knocked down, Nur77 could not stabilize HIF-α. Moreover, Nur77 could not further stabilize HIF-2α in A498/VHL stable cells, which is consistent with our finding that Nur77 indirectly stabilizes HIF-α by binding to pVHL. Thus, our results suggest that an orphan nuclear receptor Nur77 binds to pVHL, thereby stabilizes and increases HIF-α transcriptional activity under the nonhypoxic conditions.

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“…A region from Ϫ496 to Ϫ334 was identified that contains enhancers that are responsive to prostaglandin F 2␣ and Butaprost through the PKC pathway (Liang et al, 2004). The major PKC signal response element in the Nur77 promoter is an AP-1-like element (Kim et al, 2005), whereas a Nur77 promoter (Ϫ496 to ϩ67) containing four AP-1 motifs has also been reported (Uemura et al, 1995). To consider whether the AP-1 motif is involved in the PI3K/AKT/GSK3␤ signaling pathway, as well as further studying the transcription mechanisms of BP-mediated Nur77 mRNA expression, a Nur77 promoter (Ϫ496 to ϩ67) containing these four AP-1 motifs was subcloned into a luciferase reporter plasmid.…”

mentioning

confidence: 99%

“…We found that BP-induced a 30-and 50.2-fold increase in the luciferase activity of HepG2 and J5 cells, respectively, compared with the vehicle control. To investigate whether these AP-1 motifs are functional BP motifs, the protocol of Kim et al (2005) was used to mutate two AP-1 motifs (Ϫ197 to Ϫ192; Ϫ179 to Ϫ173) within the Nur77 promoter. Mutation of the AP-1 motif resulted in a dramatic decrease of BP-induced Nur77 promoter activity.…”

mentioning

confidence: 99%

The Induction of Orphan Nuclear Receptor Nur77 Expression by n-Butylenephthalide as Pharmaceuticals on Hepatocellular Carcinoma Cell Therapy

Chen¹,

Jian²,

Lin³

et al. 2008

Mol Pharmacol

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N-Butylidenephthalide (BP), isolated from the chloroform extract of Angelica sinensis, has been examined for its antitumor effects on glioblastoma multiforme brain tumors; however, little is known about its antitumor effects on hepatocellular carcinoma cells. Two hepatocellular carcinoma cell lines, HepG2 and J5, were treated with either N-butylidenephthalide or a vehicle, and cell viability and apoptosis were evaluated. Apoptosis-related mRNA and proteins expressed, including orphan receptor family Nurr1, NOR-1, and Nur77, were evaluated as well as the effect of N-butylidenephthalide in an in vivo xenograft model. N-Butylidenephthalide caused growth inhibition of both the cell lines at 25 g/ml. Furthermore, N-butylidenephthalide-induced apoptosis seems to be related to Nur77 translocation from nucleus to cytosol, which leads to cytochrome c release and caspase-3-dependent apoptosis. N-Butylidenephthalide-related tumor apoptosis was associated with phosphatidylinositol 3-kinase/protein kinase B (AKT)/glycogen synthase kinase-3␤ rather than the mitogen-activated protein kinase or protein kinase C pathway. Blockade of AKT activation enhanced proliferation inhibition and the induction of phosphor-Bcl-2 and Nur77 proteins. Besides, the increasing apoptosis by BP via transfection wild-type cAMP-response element-binding protein (CREB) into tumor cell was suppressed by dominant phosphorylation site mutation of CREB. This finding suggested CREB pathway was also partly involved in tumor apoptosis caused by BP. Administration of N-butylidenephthalide showed similar antitumoral effects in both HepG2 and J5 xenograft tumors. N-Butylidenephthalide induced apoptosis in hepatocellular carcinoma cells, both in vitro and in vivo, suggesting a potential clinical use of this compound for improving the prognosis of hepatocellular carcinoma cells.Hepatocellular carcinoma (HCC) is one of the most frequent cancers worldwide. The main curative therapies for cancer are surgery and radiation, which, in general, are only successful if the cancer is diagnosed at an early stage. CurThis work was supported National Science Council of the Republic of China

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Menin represses JunD transcriptional activity in protein kinase Cθ-mediated Nur77 expression

Cited by 37 publications

References 37 publications

Nur77 Suppresses Pulmonary Artery Smooth Muscle Cell Proliferation through Inhibition of the STAT3/Pim-1/NFAT Pathway

Nur77 Suppresses Pulmonary Artery Smooth Muscle Cell Proliferation through Inhibition of the STAT3/Pim-1/NFAT Pathway

Nur77 upregulates HIF-α by inhibiting pVHL-mediated degradation

The Induction of Orphan Nuclear Receptor Nur77 Expression by n-Butylenephthalide as Pharmaceuticals on Hepatocellular Carcinoma Cell Therapy

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