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Jo, A-Young,Kim, Mi-Young,Lee, Hyun-Seob,Rhee, Yong-Hee,Lee, Jeong-Eun,Baek, Kwang-Hyun,Park, Chang-Hwan,Koh, Hyun-Chul,Shin, Incheol,Lee, Yong-Sung,Lee, Sang-Hun Wiley Subscription Services, Inc., A Wiley Company 2009 Stem Cells Vol.27 No.9
<P>Nurr1 is a transcription factor specific for the development and maintenance of the midbrain dopamine (DA) neurons. Exogenous Nurr1 in neural precursor (NP) cells induces the differentiation of DA neurons in vitro that are capable of reversing motor dysfunctions in a rodent model for Parkinson disease. The promise of this therapeutic approach, however, is unclear due to poor cell survival and phenotype loss of DA cells after transplantation. We herein demonstrate that Nurr1 proteins undergo ubiquitin-proteasome-system-mediated degradation in differentiating NP cells. The degradation process is activated by a direct Akt-mediated phosphorylation of Nurr1 proteins and can be prevented by abolishing the Akt-target sequence in Nurr1 (Nurr1<SUP>Akt</SUP>). Overexpression of Nurr1<SUP>Akt</SUP> in NP cells yielded DA neurons in which Nurr1 protein levels were maintained for prolonged periods. The sustained Nurr1 expression endowed the Nurr1<SUP>Akt</SUP>-induced DA neurons with resistance to toxic stimuli, enhanced survival, and sustained DA phenotypes in vitro and in vivo after transplantation.</P>
Kim, Chun-Hyung,Han, Baek-Soo,Moon, Jisook,Kim, Deog-Joong,Shin, Joon,Rajan, Sreekanth,Nguyen, Quoc Toan,Sohn, Mijin,Kim, Won-Gon,Han, Minjoon,Jeong, Inhye,Kim, Kyoung-Shim,Lee, Eun-Hye,Tu, Yupeng,Naf National Academy of Sciences 2015 PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF Vol.112 No.28
<P><B>Significance</B></P><P>Parkinson’s disease (PD) is the most prevalent movement disorder with no available treatments that can stop or slow down the disease progress. Although the orphan nuclear receptor Nurr1 is a promising target for PD, it is thought to be a ligand-independent transcription factor and, so far, no small molecule has been identified that can bind to its ligand binding domain. Here, we established high throughput cell-based assays and successfully identified three Nurr1 agonists among FDA-approved drugs, all sharing an identical chemical scaffold. Remarkably, these compounds not only directly bind to Nurr1 but also ameliorate behavioral defects in a rodent model of PD. Thus, our study shows that Nurr1 could serve as a valid drug target for neuroprotective therapeutics of PD.</P><P>Parkinson’s disease (PD), primarily caused by selective degeneration of midbrain dopamine (mDA) neurons, is the most prevalent movement disorder, affecting 1–2% of the global population over the age of 65. Currently available pharmacological treatments are largely symptomatic and lose their efficacy over time with accompanying severe side effects such as dyskinesia. Thus, there is an unmet clinical need to develop mechanism-based and/or disease-modifying treatments. Based on the unique dual role of the nuclear orphan receptor Nurr1 for development and maintenance of mDA neurons and their protection from inflammation-induced death, we hypothesize that Nurr1 can be a molecular target for neuroprotective therapeutic development for PD. Here we show successful identification of Nurr1 agonists sharing an identical chemical scaffold, 4-amino-7-chloroquinoline, suggesting a critical structure–activity relationship. In particular, we found that two antimalarial drugs, amodiaquine and chloroquine stimulate the transcriptional function of Nurr1 through physical interaction with its ligand binding domain (LBD). Remarkably, these compounds were able to enhance the contrasting dual functions of Nurr1 by further increasing transcriptional activation of mDA-specific genes and further enhancing transrepression of neurotoxic proinflammatory gene expression in microglia. Importantly, these compounds significantly improved behavioral deficits in 6-hydroxydopamine lesioned rat model of PD without any detectable signs of dyskinesia-like behavior. These findings offer proof of principle that small molecules targeting the Nurr1 LBD can be used as a mechanism-based and neuroprotective strategy for PD.</P>
Yi, Sang-Hoon,He, Xi-Biao,Rhee, Yong-Hee,Park, Chang-Hwan,Takizawa, Takumi,Nakashima, Kinichi,Lee, Sang-Hun The Company of Biologists Limited 2014 Development (Cambridge) Vol.141 No.4
<P>Understanding how dopamine (DA) phenotypes are acquired in midbrain DA (mDA) neuron development is important for bioassays and cell replacement therapy for mDA neuron-associated disorders. Here, we demonstrate a feed-forward mechanism of mDA neuron development involving Nurr1 and Foxa2. Nurr1 acts as a transcription factor for DA phenotype gene expression. However, Nurr1-mediated DA gene expression was inactivated by forming a protein complex with CoREST, and then recruiting histone deacetylase 1 (Hdac1), an enzyme catalyzing histone deacetylation, to DA gene promoters. Co-expression of Nurr1 and Foxa2 was established in mDA neuron precursor cells by a positive cross-regulatory loop. In the presence of Foxa2, the Nurr1-CoREST interaction was diminished (by competitive formation of the Nurr1-Foxa2 activator complex), and CoREST-Hdac1 proteins were less enriched in DA gene promoters. Consequently, histone 3 acetylation (H3Ac), which is responsible for open chromatin structures, was strikingly increased at DA phenotype gene promoters. These data establish the interplay of Nurr1 and Foxa2 as the crucial determinant for DA phenotype acquisition during mDA neuron development.</P>
Kim, Soo Min,Cho, Soo Young,Kim, Min Woong,Roh, Seung Ryul,Shin, Hee Sun,Suh, Young Ho,Geum, Dongho,Lee, Myung Ae Korean Society for Molecular and Cellular Biology 2020 Molecules and cells Vol.43 No.6
Nuclear receptor-related 1 (Nurr1) protein has been identified as an obligatory transcription factor in midbrain dopaminergic neurogenesis, but the global set of human NURR1 target genes remains unexplored. Here, we identified direct gene targets of NURR1 by analyzing genome-wide differential expression of NURR1 together with NURR1 consensus sites in three human neural stem cell (hNSC) lines. Microarray data were validated by quantitative PCR in hNSCs and mouse embryonic brains and through comparison to published human data, including genome-wide association study hits and the BioGPS gene expression atlas. Our analysis identified ~40 NURR1 direct target genes, many of them involved in essential protein modules such as synapse formation, neuronal cell migration during brain development, and cell cycle progression and DNA replication. Specifically, expression of genes related to synapse formation and neuronal cell migration correlated tightly with NURR1 expression, whereas cell cycle progression correlated negatively with it, precisely recapitulating midbrain dopaminergic development. Overall, this systematic examination of NURR1-controlled regulatory networks provides important insights into this protein's biological functions in dopamine-based neurogenesis.
Orphan Nuclear Receptor Nurr1 as a Potential Novel Marker for Progression in Human Prostate Cancer
Wang, Jian,Yang, Jing,Zou, Ying,Huang, Guo-Liang,He, Zhi-Wei Asian Pacific Journal of Cancer Prevention 2013 Asian Pacific journal of cancer prevention Vol.14 No.3
A number of studies have indicated that Nurr1, which belongs to a novel class of orphan nuclear receptors (the NR4A family), is important for carcinogenesis. Here we investigated expression of Nurr1 protein in benign and malignant human prostate tissues and association with clinicopathologic features using immunohistochemical techniques. Moreover, we also investigated the ability of Nurr1 to influence proliferation, migration, invasion and apoptosis of human prostate cancer cells using small interfering RNA silencing. Immunohistochemical analysis revealed that the expression of Nurr1 protein was higher in prostate cancer tissues than in benign prostate tissue (P<0.001), levels being positively correlated with tumor T classification (P = 0.003), N classification (P = 0.017), M classification (P = 0.011) and the Gleason score (P = 0.020) of prostate cancer patients. In vitro, silencing of endogenous Nurr1 attenuated cell proliferation, migration and invasion, and induced apoptosis of prostate cancer cells. These results suggest that Nurr1 may be used as an indicator for prostate cancer progression and be useful for novel potential therapeutic strategies.
Nurr1 과발현에 의한 도파민신경세포 기능향상에 미치는 Mash1의 역할
강진선 ( Jin Sun Kang ),고현철 ( Hyun Chul Koh ),윤은혜 ( Eun Hye Yoon ),박장환 ( Chang Hwan Park ) 한국조직공학·재생의학회 2007 조직공학과 재생의학 Vol.4 No.1
In vitro expanded CNS precursors provide a potentially unlimited source of dopamine(DA) neurons for the experimental treatment in Parkinson`s disease. But an efficient DA differentiation from CNS precursors in vitro is limited to mesencephalic precursors isolated from early embryonic ages (embryonic day 11.5~12.5). Recently demonstrated that Nurr1, a steroid-type orphan nuclear receptor, sufficiently derives neural precursor cells, isolated from rat embryonic brains, to differentiate toward DA neurons. Nurr1-induced DA neurons, however, were less mature in their neuronal morphology and pre-synaptic functions in vitro and do not elicit behavioral recovery upon transplantation into a rodent model of Parkinson`s disease. In this study, genetic manipulation of Mash1 in the Nurr1- DA cells contributes to the acquisition of the functions to restore behavioral deficits in Parkinsonian rats, thereby these cells become a potential cell source for Parkinson`s cell therapy.
Kim Sung-Hyun,Lee Eun-Ju,Kim Myoung-Li,Park Jun-Hong,Cho Kyoungin,Jung Boo-Kyung,Kim Hee-Chul,Hwnag Sol-Ha,Lee Hoon-Taek,Ryoo Zae-Young 한국발생생물학회 2003 한국발생생물학회 학술발표대회 Vol.2003 No.1
As an effort to direct differentiation of human embryonic stem (hES, MB03) cells to dopamine-producing neuronal cells, Nurr1 was transfected using conventional transfection protocol into MB03 and examined the expression of tyrosine hydroylase (TH) after differentiation induced by retinoic acid (RA) and ascorbic acid (AA). Experimentally, cells were transfected with linearized Nurr1 cDNA in pcDNA3.1 (+)-hygovernight followed by selection in medium containing hygromycin-B (150 /ml). Expression of Nurr1 mRNA was confirmed by RT-PCR and protein by immunocytochemistry in the drug resistant clones. In order to study the effect of Nurr1 protein on the differentiation pattern of ES cells, one of the positive clones (MBNr24) was allowed to form embryoid body (EB) for 2 days and were induced to differentiate for another 4 days using RA (1 ) and AA (50 mM) (2-/4+ protocol) followed by selection in N2 medium for 10 or 20 days. After 10 days in N2 medium, cells immunoreactive to anti-GFAP, anti-TH, or anti-NF200 antibodies were 38.8%, 11%, and 20.5%, respectively. After 20 days in N2 medium, cells expressing GFAP, TH, or NF200 were 28%, 15% and 44.8%, respectively but approximately 9% of MB03 expressed TH protein when the cells were induced to differentiate using a similar prorocol, These results suggest that ectopic expression of Nurr1 enhances generation of TH+ cells as well as neuronal cells when hES cells were differentiated by 2-/4+ protocol.
Combined Nurr1 and Foxa2 roles in the therapy of Parkinson's disease
Oh, Sang-Min,Chang, Mi-Yoon,Song, Jae-Jin,Rhee, Yong-Hee,Joe, Eun-Hye,Lee, Hyun-Seob,Yi, Sang-Hoon,Lee, Sang-Hun BlackWell Publishing Ltd 2015 EMBO molecular medicine Vol.7 No.5
<P>Use of the physiological mechanisms promoting midbrain DA (mDA) neuron survival seems an appropriate option for developing treatments for Parkinson's disease (PD). mDA neurons are specifically marked by expression of the transcription factors Nurr1 and Foxa2. We show herein that Nurr1 and Foxa2 interact to protect mDA neurons against various toxic insults, but their expression is lost during aging and degenerative processes. In addition to their proposed cell-autonomous actions in mDA neurons, forced expression of these factors in neighboring glia synergistically protects degenerating mDA neurons in a paracrine mode. As a consequence of these bimodal actions, adeno-associated virus (AAV)-mediated gene delivery of Nurr1 and Foxa2 in a PD mouse model markedly protected mDA neurons and motor behaviors associated with nigrostriatal DA neurotransmission. The effects of the combined gene delivery were dramatic, highly reproducible, and sustained for at least 1 year, suggesting that expression of these factors is a promising approach in PD therapy.</P>
Lee Chang-Hyun,Cho Hwang-Yoon,Kil Kwang-Soo,Lee Gun-Soup,Yoon Ji-Yeon,Lee Young-Jae,Kim Eun-Young,Park Se-Pill,Lim Jin-Ho 한국발생생물학회 2003 한국발생생물학회 학술발표대회 Vol.2003 No.1
The purpose of this study is to evaluate an efficacy of in vitro differentiated human embryonic stem (hES, MB03) cells expressing Nurr1 in relief of symptomatic motor behavior of Parkinson's disease (PD) animal models MB03 was genetically modified to express Nurr1 protein and was induced to differentiate according to 2-/4+ protocol using retinoic acid and ascorbic acid. The differentiation-induced cells were selected for 10 to 20 days thereafter in N2 medium. Upon selection, cells expressing GFAP, TH, or NF200 were 38.8%, 11%, and 20.5%, respectively. in order to examine therapeutic effects of the differentiated cells in PD animal model, rats were unilaterally lesioned by administration of 6-kydroxydopamine HCI (6-OHDA) into medial forebrain region (MFB, AP -4.4 mm, ML 1.2 mm, DV 78 mm with incision bar set at -2.4 mm), as a reference to bregma and the surface of the skull. Confirmation of successful lesion by apomorphine-induced rotational behavior, differentiated cells were transplanted into the striatum (AP 1.0, ML 3.5, DV -5.0; AP 0.6, ML 2.5, DV -4.5). Improvements of asymmetric motor behavior by the transplantation were examined every two weeks after the surgery. In two weeks, numbers of rotation by the experimental rats were (P<0.05) of the number before transplantation, however, the ratio increased slightly to in six weeks. In contrast, the ratio of sham-grafted animals ranged from 112.3+8.5% to 139.2+28.9% during the examination. Immunohistochemical studies further confirmed the presence, survival, migration, and expression of TH of the transplanted human cells.