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https://www.readbyqxmd.com/read/29884904/drug-targeting-of-nr4a-nuclear-receptors-for-treatment-of-acute-myeloid-leukemia
#1
Seth P Boudreaux, Ryan P Duren, Steven G Call, Loc Nguyen, Pablo R Freire, Padmini Narayanan, Michele S Redell, Orla M Conneely
NR4As are AML tumor suppressors that are frequently silenced in human acute myeloid leukemia (AML). Despite their potential as novel targets for therapeutic intervention, mechanisms of NR4A silencing and strategies for their reactivation remain poorly defined. Here we show that NR4A silencing in AML occurs through blockade of transcriptional elongation rather than epigenetic promoter silencing. By intersection of NR4A-regulated gene signatures captured upon acute, exogenous expression of NR4As in human AML cells with in silico chemical genomics screening, we identify several FDA-approved drugs including dihydroergotamine (DHE) that reactivate NR4A expression and regulate NR4A-dependent gene signatures...
June 8, 2018: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/29777725/strain-related-differences-in-mouse-lung-gene-expression-over-a-two-year-period-of-inhalation-exposure-to-styrene-relevance-to-human-risk-assessment
#2
Melvin E Andersen, George Cruzan, Michael B Black, Salil N Pendse, Darol E Dodd, James S Bus, Satinder S Sarang, Marcy I Banton, Robbie Waites, Debra B Layko, Patrick D McMullen
Both CD-1 and C57BL/6 wildtype (C57BL/6-WT) mice show equivalent short-term lung toxicity from exposures to styrene, while long-term tumor responses are greater in CD-1 mice. We analyzed lung gene expression from styrene exposures lasting from 1-day to 2-years in male mice from these two strains, including a Cyp2f2(-/-) knockout (C57BL/6-KO) and a Cyp2F1/2A13/2B6 transgenic mouse (C57BL/6-TG). With short term exposures (1-day to 1-week), CD-1 and C57BL/6-WT mice had thousands of differentially expressed genes (DEGs), consistent with changes in pathways for cell proliferation, cellular lipid metabolism, DNA-replication and inflammation...
May 16, 2018: Regulatory Toxicology and Pharmacology: RTP
https://www.readbyqxmd.com/read/29738496/endogenous-purification-of-nr4a2-nurr1-identified-poly-adp-ribose-polymerase-1-as-a-prime-coregulator-in-human-adrenocortical-h295r-cells
#3
Erika Noro, Atsushi Yokoyama, Makoto Kobayashi, Hiroki Shimada, Susumu Suzuki, Mari Hosokawa, Tomohiro Takehara, Rehana Parvin, Hiroki Shima, Kazuhiko Igarashi, Akira Sugawara
Aldosterone is synthesized in zona glomerulosa of adrenal cortex in response to angiotensin II. This stimulation transcriptionally induces expression of a series of steroidogenic genes such as HSD3B and CYP11B2 via NR4A (nuclear receptor subfamily 4 group A) nuclear receptors and ATF (activating transcription factor) family transcription factors. Nurr1 belongs to the NR4A family and is regarded as an orphan nuclear receptor. The physiological significance of Nurr1 in aldosterone production in adrenal cortex has been well studied...
May 8, 2018: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/29726098/mef2-induction-of-the-immediate-early-gene-hr38-nr4a-is-terminated-by-sirt1-to-promote-ethanol-tolerance
#4
Pratik Adhikari, Donnoban Orozco, Harpreet Randhawa, Fred W Wolf
Drug naïve animals given a single dose of ethanol show changed responses to subsequent doses, including the development of ethanol tolerance and ethanol preference. These simple forms of behavioral plasticity are due in part to changes in gene expression and neuronal properties. Surprisingly little is known about how ethanol initiates changes in gene expression or what the changes do. Here we demonstrate a role in ethanol plasticity for Hr38, the sole Drosophila homolog of the mammalian Nr4a1/2/3 class of immediate early response transcription factors...
May 3, 2018: Genes, Brain, and Behavior
https://www.readbyqxmd.com/read/29559474/inhibition-of-nr4a-receptors-enhances-anti-tumor-immunity-by-breaking-treg-mediated-immune-tolerance
#5
Sana Hibino, Shunsuke Chikuma, Taisuke Kondo, Minako Ito, Hiroko Nakatsukasa, Setsuko Omata-Mise, Akihiko Yoshimura
Enhanced infiltration of regulatory T (Treg) cells into tumor tissue is detrimental to cancer patients and closely associated with poor prognosis as they create an immunosuppressive state that suppresses anti-tumor immune responses. Therefore, breaking Treg-mediated immune tolerance is important when considering cancer immunotherapy. Here we show that the Nr4a nuclear receptors, key transcription factors maintaining Treg cell genetic programs, contribute to Treg-mediated suppression of anti-tumor immunity in the tumor microenvironment...
March 20, 2018: Cancer Research
https://www.readbyqxmd.com/read/29531824/nr4a2-protects-cardiomyocytes-against-myocardial-infarction-injury-by-promoting-autophagy
#6
Honghong Liu, Pingping Liu, Xingxing Shi, Deling Yin, Jing Zhao
Myocardial infarction (MI), characterized by ischemia-induced cardiomyocyte apoptosis, is the leading cause of mortality worldwide. NR4A2, a member of the NR4A orphan nucleus receptor family, is upregulated in mouse hearts with MI injury. Furthermore, NR4A2 knockdown aggravates heart injury as evidenced by enlarged hearts and increased apoptosis. To elucidate the underlying mechanisms of NR4A2-regulated apoptosis, we used H9c2 cardiomyocytes deprived of serum and neonatal rat cardiomyocytes (NRCMs) exposed to hypoxia to mimic ischemic conditions in vivo...
December 2018: Cell Death Discovery
https://www.readbyqxmd.com/read/29527211/the-footprints-of-poly-autoimmunity-evidence-for-common-biological-factors-involved-in-multiple-sclerosis-and-hashimoto-s-thyroiditis
#7
Simona Perga, Serena Martire, Francesca Montarolo, Ilaria Giordani, Michela Spadaro, Gabriele Bono, Stefania Corvisieri, Ilaria Messuti, Giancarlo Panzica, Fabio Orlandi, Antonio Bertolotto
Autoimmune diseases are a diverse group of chronic disorders and affect a multitude of organs and systems. However, the existence of common pathophysiological mechanisms is hypothesized and reports of shared risk are emerging as well. In this regard, patients with multiple sclerosis (MS) have been shown to have an increased susceptibility to develop chronic autoimmune thyroid diseases, in particular Hashimoto's thyroiditis (HT), suggesting an autoimmune predisposition. However, studies comparing such different pathologies of autoimmune origin are still missing till date...
2018: Frontiers in Immunology
https://www.readbyqxmd.com/read/29526770/hr38-an-ortholog-of-nr4a-family-nuclear-receptors-mediates-20-hydroxyecdysone-regulation-of-carbohydrate-metabolism-during-mosquito-reproduction
#8
Dujuan Dong, Yang Zhang, Vlastimil Smykal, Lin Ling, Alexander S Raikhel
The Aedes aegypti mosquito is the principal vector for many dangerous human viral diseases. Carbohydrate metabolism (CM) is essential for supplying the energy necessary for host seeking, blood digestion and rapid egg development of this vector insect. The steroid hormone 20-hydroxyecdysone (20E) and the ecdysone receptor (EcR) are important regulators of CM, coordinating it with female reproductive events. We report here that the NR4A nuclear receptor AHR38 plays a critical role in mediating these actions of 20E and EcR...
May 2018: Insect Biochemistry and Molecular Biology
https://www.readbyqxmd.com/read/29448246/effect-of-mst1-on-endometriosis-apoptosis-and-migration-role-of-drp1-related-mitochondrial-fission-and-parkin-required-mitophagy
#9
Qingdong Zhao, Mingxia Ye, Wen Yang, Min Wang, Mingxia Li, Chenglei Gu, Luyang Zhao, Zhe Zhang, Weidong Han, Wensheng Fan, Yuanguang Meng
BACKGROUND/AIMS: Mitochondrial homeostasis is implicated in the development and progression of endometriosis through poorly defined mechanisms. Mst1 is the major growth suppressor related to cancer migration, apoptosis and proliferation. However, whether Mst1 is involved in endometriosis apoptosis and migration via regulating the mitochondrial function remains to be elucidated. METHODS: Expression of Mst1 in endometriosis was examined via western blots. Cellular apoptosis was detected via MTT and TUNEL assay...
2018: Cellular Physiology and Biochemistry
https://www.readbyqxmd.com/read/29368971/ligand-dependent-transcriptional-induction-of-lethal-autophagy-a-new-perspective-for-cancer-treatment
#10
Sandrine Silvente-Poirot, Gregory Segala, Mathias C Poirot, Marc Poirot
Dendrogenin A (DDA) is a mammalian metabolite that displays anticancer and chemopreventive properties in mice. At the cancer cell level, DDA induces differentiation and death. We investigated herein the nature of DDA cytoxicity in cancer cells. We showed that DDA triggers biochemical and cellular features of macroautophagy/autophagy and that autophagy is cytotoxic. DDA induces both the accumulation of pro-lysosomal sterols and stimulates the expression of regulators of autophagy such as NR4A, LC3 and TFEB through binding to the liver X receptor (LXR), a ligand-dependent transcription factor consisting of 2 isoforms, NR1H2 and NR1H3...
2018: Autophagy
https://www.readbyqxmd.com/read/29343483/nr4a1-and-nr4a3-restrict-hsc-proliferation-via-reciprocal-regulation-of-c-ebp%C3%AE-and-inflammatory-signaling
#11
Pablo R Freire, Orla M Conneely
Members of the NR4A subfamily of nuclear receptors have complex, overlapping roles during hematopoietic cell development and also function as tumor suppressors of hematologic malignancies. We previously identified NR4A1 and NR4A3 (NR4A1/3) as functionally redundant suppressors of acute myeloid leukemia (AML) development. However, their role in hematopoietic stem cell (HSC) homeostasis remains to be disclosed. Using a conditional Nr4a1 / Nr4a3 knockout mouse (CDKO), we show that codepletion of NR4A1/3 promotes acute changes in HSC homeostasis including loss of HSC quiescence, accumulation of oxidative stress, and DNA damage while maintaining stem cell regenerative and differentiation capacity...
March 8, 2018: Blood
https://www.readbyqxmd.com/read/29145494/global-analysis-of-gene-expression-mediated-by-ox1-orexin-receptor-signaling-in-a-hypothalamic-cell-line
#12
Eric Koesema, Thomas Kodadek
The orexins and their cognate G-protein coupled receptors have been widely studied due to their associations with various behaviors and cellular processes. However, the detailed downstream signaling cascades that mediate these effects are not completely understood. We report the generation of a neuronal model cell line that stably expresses the OX1 orexin receptor (OX1) and an RNA-Seq analysis of changes in gene expression seen upon receptor activation. Upon treatment with orexin, several families of related transcription factors are transcriptionally regulated, including the early growth response genes (Egr), the Kruppel-like factors (Klf), and the Nr4a subgroup of nuclear hormone receptors...
2017: PloS One
https://www.readbyqxmd.com/read/29047330/deletion-of-the-nr4a-nuclear-receptor-nor1-in-hematopoietic-stem-cells-reduces-inflammation-but-not-abdominal-aortic-aneurysm-formation
#13
Hua Qing, Karrie L Jones, Elizabeth B Heywood, Hong Lu, Alan Daugherty, Dennis Bruemmer
BACKGROUND: The NR4A3 orphan nuclear hormone receptor, NOR1, functions as a constitutively active transcription factor to regulate inflammation, proliferation, and cell survival during pathological vascular remodeling. Inflammatory processes represent key mechanisms leading to abdominal aortic aneurysm (AAA) formation. However, a role of NOR1 in AAA formation has not been investigated previously. METHODS: Inflammatory gene expression was analyzed in bone marrow-derived macrophages isolated from NOR1-deficient mice...
October 18, 2017: BMC Cardiovascular Disorders
https://www.readbyqxmd.com/read/29026837/binding-site-analysis-of-the-caenorhabditis-elegans-nr4a-nuclear-receptor-nhr-6-during-development
#14
Brandon Praslicka, Jeremy S Harmson, Joohyun Kim, Vittobai Rashika Rangaraj, Aikseng Ooi, Chris R Gissendanner
Members of the NR4A subfamily of nuclear receptors make up a highly conserved, functionally diverse group of transcription factors implicated in a multitude of cellular processes such as proliferation, differentiation, apoptosis, metabolism and DNA repair. The gene nhr-6, which encodes the sole C. elegans NR4A nuclear receptor homolog, has a critical role in organogenesis and regulates the development of the spermatheca organ system. Our previous work revealed that nhr-6 is required for spermatheca cell divisions in late L3 and early L4 and spermatheca cell differentiation during the mid L4 stage...
2017: Nuclear Receptor Research
https://www.readbyqxmd.com/read/28951217/assessing-molecular-initiating-events-mies-key-events-kes-and-modulating-factors-mfs-for-styrene-responses-in-mouse-lungs-using-whole-genome-gene-expression-profiling-following-1-day-and-multi-week-exposures
#15
Melvin E Andersen, George Cruzan, Michael B Black, Salil N Pendse, Darol Dodd, James S Bus, Satinder S Sarang, Marcy I Banton, Robbie Waites, Patrick D McMullen
Styrene increased lung tumors in mice at chronic inhalation exposures of 20ppm and greater. MIEs, KEs and MFs were examined using gene expression in three strains of male mice (the parental C57BL/6 strain, a CYP2F2(-/-) knock out and a CYP2F2(-/-) transgenic containing human CYP2F1, 2A13 and 2B6). Exposures were for 1-day and 1, 4 and 26weeks. After 1-day exposures at 1, 5, 10, 20, 40 and 120ppm significant increases in differentially expressed genes (DEGs) occurred only in parental strain lungs where there was already an increase in DEGs at 5ppm and then many thousands of DEGs by 120ppm...
November 15, 2017: Toxicology and Applied Pharmacology
https://www.readbyqxmd.com/read/28893954/the-orphan-nuclear-receptor-nr4a3-is-involved-in-the-function-of-dendritic-cells
#16
Masanori Nagaoka, Takuya Yashiro, Yuna Uchida, Tomoaki Ando, Mutsuko Hara, Hajime Arai, Hideoki Ogawa, Ko Okumura, Kazumi Kasakura, Chiharu Nishiyama
NR4A3/NOR1 belongs to the NR4A subfamily of the nuclear hormone receptor superfamily, which is activated in a ligand-independent manner. To examine the role of NR4A3 in gene expression of dendritic cells (DCs), we introduced NR4A3 small interfering RNA (siRNA) into bone marrow-derived DCs and determined the expression levels of mRNA and proteins of cytokines, cell surface molecules, NF-κB signaling-related proteins, and transcription factors. The expression level of NR4A3 was markedly upregulated by TLR-mediated stimulation in DCs...
October 15, 2017: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/28844671/transcriptional-profiling-of-human-femoral-mesenchymal-stem-cells-in-osteoporosis-and-its-association-with-adipogenesis
#17
Yong Jun Choi, Insun Song, Yilan Jin, Hyun-Seok Jin, Hyung Min Ji, Seon-Yong Jeong, Ye-Yeon Won, Yoon-Sok Chung
Genetic alterations are major contributing factors in the development of osteoporosis. Osteoblasts and adipocytes share a common origin, mesenchymal stem cells (MSCs), and their genetic determinants might be important in the relationship between osteoporosis and obesity. In the present study, we aimed to isolate differentially expressed genes (DEGs) in osteoporosis and normal controls using human MSCs, and elucidate the common pathways and genes related to osteoporosis and adipogenesis. Human MSCs were obtained from the bone marrow of femurs from postmenopausal women during orthopedic surgeries...
October 20, 2017: Gene
https://www.readbyqxmd.com/read/28838938/nr4a-proteins-and-neutrophil-lifespan
#18
COMMENT
Lee-Ann H Allen
No abstract text is available yet for this article.
August 24, 2017: Blood
https://www.readbyqxmd.com/read/28808448/relevance-of-the-nr4a-sub-family-of-nuclear-orphan-receptors-in-trophoblastic-bewo-cell-differentiation
#19
Sudha Saryu Malhotra, Satish Kumar Gupta
Nur-77, a member of the NR4A sub-family of nuclear orphan receptors, is downregulated in the placentae of pre-eclamptic women. Here, we investigate the relevance of Nor-1, Nurr-1 and Nur-77 in trophoblastic cell differentiation. Their transcript levels were found to be significantly upregulated in BeWo cells treated with forskolin. The maximum increase was observed after 2 h, with a second peak in the expression levels after 48 h. The expression of NR4A sub-family members was also found to be upregulated in BeWo cells after treatment with hCG and GnRH...
2017: Cellular & Molecular Biology Letters
https://www.readbyqxmd.com/read/28804711/annotation-of-the-nuclear-receptors-in-an-estuarine-fish-species-fundulus-heteroclitus
#20
William S Baldwin, W Tyler Boswell, Gautam Ginjupalli, Elizabeth J Litoff
The nuclear receptors (NRs) are ligand-dependent transcription factors that respond to various internal as well as external cues such as nutrients, pheromones, and steroid hormones that play crucial roles in regulation and maintenance of homeostasis and orchestrating the physiological and stress responses of an organism. We annotated the Fundulus heteroclitus (mummichog; Atlantic killifish) nuclear receptors. Mummichog are a non-migratory, estuarine fish with a limited home range often used in environmental research as a field model for studying ecological and evolutionary responses to variable environmental conditions such as salinity, oxygen, temperature, pH, and toxic compounds because of their hardiness...
2017: Nuclear Receptor Research
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