A Regulatory Circuit Mediating Convergence between Nurr1 Transcriptional Regulation and Wnt Signaling

Kitagawa, Hirochika; Ray, William J.; Glantschnig, Helmut; Nantermet, Pascale V.; Yu, Yuanjiang; Leu, Chih‐Tai; Harada, Satoru; Kato, Shigeaki; Freedman, Leonard P.

doi:10.1128/mcb.00409-07

Cited by 50 publications

(57 citation statements)

References 60 publications

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“…29 In a recent report, Nr4a2 has been shown to interact with Wnt signaling via b-catenin in the establishment and development of the nervous system. 30 More importantly, Nr4a2 was reported to be critical for induction and survival of dopaminergic neurons. 15 Nr4a2 +/À mice appear normal at birth, but show motor abnormality as a result of reduce numbers of dopaminergic neurons.…”

Section: Discussionmentioning

confidence: 99%

Genome-wide gene expression profiling of the Angelman syndrome mice with Ube3a mutation

Low

Chen

2010

Eur J Hum Genet

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Angelman syndrome (AS) is a human neurological disorder caused by lack of maternal UBE3A expression in the brain. UBE3A is known to function as both an ubiquitin-protein ligase (E3) and a coactivator for steroid receptors. Many ubiquitin targets, as well as interacting partners, of UBE3A have been identified. However, the pathogenesis of AS, and how deficiency of maternal UBE3A can upset cellular homeostasis, remains vague. In this study, we performed a genome-wide microarray analysis on the maternal Ube3a-deficient (Ube3a mÀ/p+ ) AS mouse to search for genes affected in the absence of Ube3a. We observed 64 differentially expressed transcripts (7 upregulated and 57 downregulated) showing more than 1.5-fold differences in expression (Po0.05). Pathway analysis shows that these genes are implicated in three major networks associated with cell signaling, nervous system development and cell death. Using quantitative reverse-transcription PCR, we validated the differential expression of genes (Fgf7, Glra1, Mc1r, Nr4a2, Slc5a7 and Epha6) that show functional relevance to AS phenotype. We also show that the protein level of melanocortin 1 receptor (Mc1r) and nuclear receptor subfamily 4, group A, member 2 (Nr4a2) in the AS mice cerebellum is decreased relative to that of the wild-type mice. Consistent with this finding, expression of small-interfering RNA that targets Ube3a in P19 cells caused downregulation of Mc1r and Nr4a2, whereas overexpression of Ube3a results in the upregulation of Mc1r and Nr4a2. These observation help in providing insights into the genesis of neurodevelopmental phenotype of AS and highlight specific area for future research.

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Section: Discussionmentioning

confidence: 99%

Genome-wide gene expression profiling of the Angelman syndrome mice with Ube3a mutation

Low

Chen

2010

Eur J Hum Genet

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“…In vitro, NR4A2 inhibits p53-mediated induction of downstream proapoptotic genes like BAX, a proapoptotic member of the Bcl-2 family (6). NR4A2 also inhibits apoptosis via convergence with Wnt and mitogen-activated protein kinase (MAPK) pathways (7,8). Kitagawa and colleagues have reported that b-catenin binds NR4A2, releasing NR4A2 from the corepressor protein Lef-1 in 293F cells, allowing transcription of downstream Wnt and NR4A2 targets.…”

Section: Apoptosismentioning

confidence: 99%

“…Physiologically, these interactions are required for normal neuronal development and the survival of dopaminergic neurons (7). NR4A receptors and b-catenin modulate each other's transcriptional activity in a cell-specific manner (7,9). In colon cancer cell lines, a bile acid carcinogen (deoxycholic acid) has been shown to stimulate b-catenin-dependent increased expression of NR4A1 (10).…”

Section: Apoptosismentioning

confidence: 99%

Molecular Pathways: The Role of NR4A Orphan Nuclear Receptors in Cancer

Mohan

Aherne

Rogers

et al. 2012

Clinical Cancer Research

158

142

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Nuclear receptors are of integral importance in carcinogenesis. Manipulation of classic ligand-activated nuclear receptors, such as estrogen receptor blockade in breast cancer, is an important established cancer therapy. Orphan nuclear receptors, such as nuclear family 4 subgroup A (NR4A) receptors, have no known natural ligand(s). These elusive receptors are increasingly recognized as molecular switches in cell survival and a molecular link between inflammation and cancer. NR4A receptors act as transcription factors, altering expression of downstream genes in apoptosis (Fas-ligand, TRAIL), proliferation, DNA repair, metabolism, cell migration, inflammation (interleukin-8), and angiogenesis (VEGF). NR4A receptors are modulated by multiple cell-signaling pathways, including protein kinase A/CREB, NF-kB, phosphoinositide 3-kinase/AKT, c-jun-NH 2 -kinase, Wnt, and mitogen-activated protein kinase pathways. NR4A receptor effects are context and tissue specific, influenced by their levels of expression, posttranslational modification, and interaction with other transcription factors (RXR, PPAR-¡). The subcellular location of NR4A "nuclear receptors" is also important functionally; novel roles have been described in the cytoplasm where NR4A proteins act both indirectly and directly on the mitochondria to promote apoptosis via Bcl-2. NR4A receptors are implicated in a wide variety of malignancies, including breast, lung, colon, bladder, and prostate cancer; glioblastoma multiforme; sarcoma; and acute and/or chronic myeloid leukemia. NR4A receptors modulate response to conventional chemotherapy and represent an exciting frontier for chemotherapeutic intervention, as novel agents targeting NR4A receptors have now been developed. This review provides a concise clinical overview of current knowledge of NR4A signaling in cancer and the potential for therapeutic manipulation.

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“…Another nuclear receptor, NURR1, has been shown to both repress and activate transcription of Wnt targets via interactions with the TCF/LEF complex and b-catenin (Kitagawa et al 2007). In that case, binding of b-catenin to NURR1 disrupts co-repressor complexes, allowing co-activators to bind and activate.…”

Section: Erra As a Regulator Of Wnt Signalingmentioning

confidence: 99%

Estrogen-related receptor α regulates osteoblast differentiation via Wnt/β-catenin signaling

Auld¹,

Berasi²,

Liu³

et al. 2012

Journal of Molecular Endocrinology

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Based on its homology to the estrogen receptor and its roles in osteoblast and chondrocyte differentiation, the orphan nuclear receptor estrogen-related receptor a (ERRa (ESRRA)) is an intriguing therapeutic target for osteoporosis and other bone diseases. The objective of this study was to better characterize the molecular mechanisms by which ERRa modulates osteoblastogenesis. Experiments from multiple systems demonstrated that ERRa modulates Wnt signaling, a crucial pathway for proper regulation of bone development. This was validated using a Wnt-luciferase reporter, where ERRa showed co-activator-dependent (peroxisome proliferator-activated receptor gamma co-activator 1a, PGC-1a) stimulatory effects. Interestingly, knockdown of ERRa expression also enhanced WNT signaling. In combination, these data indicated that ERRa could serve to either activate or repress Wnt signaling depending on the presence or absence of its co-activator PGC-1a. The observed Wnt pathway modulation was cell intrinsic and did not alter b-catenin nuclear translocation but was dependent on DNA binding of ERRa. We also found that expression of active ERRa correlated with Wnt pathway effects on osteoblastic differentiation in two cell types, consistent with a role for ERRa in modulating the Wnt pathway. In conclusion, this work identifies ERRa, in conjunction with co-activators such as PGC-1a, as a new regulator of the Wnt-signaling pathway during osteoblast differentiation, through a cell-intrinsic mechanism not affecting b-catenin nuclear translocation.

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A Regulatory Circuit Mediating Convergence between Nurr1 Transcriptional Regulation and Wnt Signaling

Cited by 50 publications

References 60 publications

Genome-wide gene expression profiling of the Angelman syndrome mice with Ube3a mutation

Genome-wide gene expression profiling of the Angelman syndrome mice with Ube3a mutation

Molecular Pathways: The Role of NR4A Orphan Nuclear Receptors in Cancer

Estrogen-related receptor α regulates osteoblast differentiation via Wnt/β-catenin signaling

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