Hormonal regulation and functional role of Drosophila E75A orphan nuclear receptor in the juvenile hormone signaling pathway

In 2009 we reported that depletion of Dicer-1, the enzyme that catalyzes the final step of miRNA biosynthesis, prevents metamorphosis inBlattella germanica. However, the precise regulatory roles of miRNAs in the process have remained elusive. In the present work, we have observed that Dicer-1 depletion results in an increase of mRNA levels of Krüppel homolog 1 (Kr-h1), a juvenile hormone-dependent transcription factor that represses metamorphosis, and that depletion of Kr-h1 expression in Dicer-1 knockdown individuals rescues metamorphosis. We have also found that the 3′UTR of Kr-h1 mRNA contains a functional binding site for miR-2 family miRNAs (for miR-2, miR-13a, and miR-13b). These data suggest that metamorphosis impairment caused by Dicer-1 and miRNA depletion is due to a deregulation of Kr-h1 expression and that this deregulation is derived from a deficiency of miR-2 miRNAs. We corroborated this by treating the last nymphal instar ofB. germanicawith an miR-2 inhibitor, which impaired metamorphosis, and by treating Dicer-1-depleted individuals with an miR-2 mimic to allow nymphal-to-adult metamorphosis to proceed. Taken together, the data indicate that miR-2 miRNAs scavenge Kr-h1 transcripts when the transition from nymph to adult should be taking place, thus crucially contributing to the correct culmination of metamorphosis.

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The Drosophila Orphan Nuclear Receptor DHR38 Mediates an Atypical Ecdysteroid Signaling Pathway

Cell ◽

10.1016/s0092-8674(03)00420-3 ◽

2003 ◽

Vol 113 (6) ◽

pp. 731-742 ◽

Cited By ~ 160

Author(s):

Keith D. Baker ◽

Lisa M. Shewchuk ◽

Tatiana Kozlova ◽

Makoto Makishima ◽

Annie Hassell ◽

...

Keyword(s):

Signaling Pathway ◽

Nuclear Receptor ◽

Orphan Nuclear Receptor

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The orphan nuclear receptor Nurr1 agonist amodiaquine mediates neuroprotective effects in 6-OHDA Parkinson’s disease animal model by enhancing the phosphorylation of P38 mitogen-activated kinase but not PI3K/AKT signaling pathway

Metabolic Brain Disease ◽

10.1007/s11011-021-00670-2 ◽

2021 ◽

Vol 36 (4) ◽

pp. 609-625 ◽

Cited By ~ 1

Author(s):

Piniel Alphayo Kambey ◽

Ma Chengcheng ◽

Guo Xiaoxiao ◽

Ayanlaja Abiola Abdulrahman ◽

Kouminin Kanwore ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Animal Model ◽

Signaling Pathway ◽

Nuclear Receptor ◽

Akt Signaling ◽

Orphan Nuclear Receptor ◽

Akt Signaling Pathway ◽

Neuroprotective Effects

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The lncRNA ADAMTS9-AS2 Regulates RPL22 to Modulate TNBC Progression via Controlling the TGF-β Signaling Pathway

Frontiers in Oncology ◽

10.3389/fonc.2021.654472 ◽

2021 ◽

Vol 11 ◽

Author(s):

Kan Ni ◽

Zhiqi Huang ◽

Yichun Zhu ◽

Dandan Xue ◽

Qin Jin ◽

...

Keyword(s):

Signaling Pathway ◽

Functional Role ◽

Cancer Type ◽

Cycle Arrest ◽

Transcriptomic Sequencing ◽

Non Coding Rnas ◽

Functional Relevance

BackgroundLong non-coding RNAs (lncRNAs) are key regulators of triple-negative breast cancer (TNBC) progression, but further work is needed to fully understand the functional relevance of these non-coding RNAs in this cancer type. Herein, we explored the functional role of the lncRNA ADAMTS9-AS2 in TNBC.MethodsNext-generation sequencing was conducted to compare the expression of different lncRNAs in TNBC tumor and paracancerous tissues, after which ADAMTS9-AS2differential expression in these tumor tissues was evaluated via qPCR. The functional role of this lncRNA was assessed by overexpressing it in vitro and in vivo. FISH and PCR were used to assess the localization of ADAMTS9-AS2within cells. Downstream targets of ADAMTS9-AS2 signaling were identified via RNA pulldown assays and transcriptomic sequencing.ResultsThe expression ofADAMTS9-AS2 was decreased in TNBC tumor samples (P < 0.05), with such downregulation being correlated with TNM stage, age, and tumor size. Overexpressing ADAMTS9-AS2 promoted the apoptotic death and cell cycle arrest of tumor cells in vitro and inhibited tumor growth in vivo. From a mechanistic perspective, ADAMTS9-AS2 was found to control the expression of RPL22 and to thereby modulate TGF-β signaling to control TNBC progression.ConclusionADAMTS9-AS2 controls the expression of RPL22 and thereby regulates TNBC malignancy via the TGF-β signaling pathway.

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NCAM and attached polysialic acid affect behaviors of breast epithelial cells through differential signaling pathways

10.21203/rs.2.24259/v2 ◽

2020 ◽

Author(s):

Lin Cao ◽

Xin Wang ◽

Juhong Yang ◽

Jia Guo ◽

Xiang Li ◽

...

Keyword(s):

Breast Cancer ◽

Cell Adhesion ◽

Epithelial Cells ◽

Signaling Pathway ◽

Functional Role ◽

Polysialic Acid ◽

Breast Epithelial Cells ◽

Differential Signaling ◽

Breast Epithelial

Abstract Background Neural cell adhesion molecule (NCAM), a common mammalian cell surface glycoprotein, is the major substrate of polysialic acid (polySia). Polysialylated NCAM occurs in many types of cancer, but rarely in normal adult tissues. Epithelial-mesenchymal transition (EMT) is an important process contributing to tumor metastasis. The functional role of NCAM hypersialylation in EMT is unclear. Method Expression of NCAM and polysialylated NCAM in breast cancer progression were evaluated by western blot (WB), immunohistochemistry, semi-quantitative PCR and immunoprecipitation (IP). Overexpression of NCAM-140 and ST8SiaII were performed to assess the functional role of NCAM hypersialylation by liposome transfection. Cell proliferation ability was investigated with MTT assay. Transwell and wound closure assay were conducted to evaluate cell migratory ability. Phagokinetic gold sol assay and cell adhesion assay were performed to assess cell motility ability and cell adhesion ability, respectively. Furthermore, WB and IP were used to reveal the activated signaling pathway. Results The present study indicates that NCAM and attached polysialic acid affect behaviors of breast epithelial cells through differential signaling pathways, based on the following observations: (i) NCAM and polysialylated NCAM were aberrantly regulated in breast cancer cells; (ii) NCAM and polysialylated NCAM expression were upregulated in normal breast epithelial cells undergoing EMT; (iii) NCAM overexpression induced EMT in breast epithelial cells; (iv) NCAM promoted cell proliferation and migration through activation of a β-catenin/slug signaling pathway; (v) modification of polySia attached to NCAM inhibited cell adhesion and promoted cell motility through activation of an EGFR/STAT3 pathway. Conclusion This study demonstrates that NCAM and polysialylated NCAM facilitate different signaling pathway and affect different cell behaviors. Switching between the NCAM-mediated pathways appeared to depend on polySia decoration.

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The Transcriptional Repressor Orphan Nuclear Receptor TLX Is Responsive to Caffeine and Istradefylline

10.26434/chemrxiv.14558121.v1 ◽

2021 ◽

Author(s):

Giuseppe Faudone ◽

Whitney Kilu ◽

Xiaomin Ni ◽

Apirat Chaikuad ◽

Sridhar Sreeramulu ◽

...

Keyword(s):

Nuclear Receptors ◽

Nuclear Receptor ◽

Drug Target ◽

Protein Complexes ◽

Orphan Nuclear Receptor ◽

Essential Factor ◽

Stem Cell Survival ◽

Functional Understanding ◽

Repressor Activity

The orphan nuclear receptor TLX is expressed almost exclusively in neural stem cells. TLX acts as an essential factor for neural stem cell survival and is hence considered as a promising drug target in neurodegeneration. However, few studies have characterized the roles of TLX due to a lack of ligands and limited functional understanding. Here, we identify caffeine and istradefylline as TLX ligands that counteract the receptor’s intrinsic repressor activity in reporter gene assays and modulate TLX regulated SIRT1 and p21 expression. Mutagenesis of residues lining a cavity within the TLX ligand binding domain altered activity of these ligands suggesting direct interactions with helix 5. Using istradefylline as a tool compound, we observed ligand-sensitive recruitment of the co-repressor SMRT and heterodimerization of TLX with RXR. Both protein-protein complexes evolve as factors that modulate TLX function and suggest an unprecedented role of TLX in directly repressing other nuclear receptors.

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