H19 potentiates let-7 family expression through reducing PTBP1 binding to their precursors in cholestasis

Zhang, Li; Yang, Zhihong; Huang, Wendong; Wu, Jiang

doi:10.1038/s41419-019-1423-6

Cited by 38 publications

(34 citation statements)

References 56 publications

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“…LncRNAs typically regulate target genes via interactions with RNA binding proteins [ 32 , 33 ]. To further determine the mechanism by which H19 regulates metabolism, we used a biotinylated H19 probe to perform an RNA pull-down assay, followed by silver staining and mass spectrometry (Fig.…”

Section: Resultsmentioning

confidence: 99%

LncRNAH19 improves insulin resistance in skeletal muscle by regulating heterogeneous nuclear ribonucleoprotein A1

Gui

Zhu

et al. 2020

Cell Commun Signal

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Background Skeletal muscle is essential for glucose and lipid metabolism. Growing evidence reveals the importance of long non-coding RNAs (LncRNAs) in metabolism. This study aimed to investigate the function of LncRNA H19 (H19) in lipid metabolism of skeletal muscle and its potential mechanisms. Methods Glucose tolerance, serum insulin and lipid content in serum and skeletal muscle were determined in control and H19-overexpressed db/db mice. Lipid metabolism was evaluated in H19-overexpressed or H19-silencing muscle cells by detecting lipid contents and mitochondria related functions. The underlying mechanisms were explored by RNA pull-down, mass spectrometry and RNA immunoprecipitation (RIP). Results H19 was downregulated in skeletal muscle of db/db mice. H19 overexpression in db/db mice inhibited lipid ectopic deposition in skeletal muscle, meanwhile improved glucose intolerance and insulin resistance as compared with control db/db mice treated with ad-GFP. Furthermore, overexpression of H19 reversed FFA-induced lipid accumulation and increased cellular respiration in muscle cells, while H19 knockdown exhibited opposite effects in muscle cells. Mechanistically, H19 interacted with heterogeneous nuclear ribonucleoprotein (hnRNPA1) which was validated by RNA pulldown and RIP analysis, which increased translation of fatty acid oxidation closely related genes PGC1a and CPT1b. Conclusion Our data suggest that overexpression of H19 ameliorates insulin resistance by reducing ectopic lipid accumulation in skeletal muscle. The possible underlying mechanisms are that overexpression of lncRNAH19 promotes fatty acids oxidation via targeting of hnRNPA1.

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Section: Resultsmentioning

confidence: 99%

LncRNAH19 improves insulin resistance in skeletal muscle by regulating heterogeneous nuclear ribonucleoprotein A1

Gui

Zhu

et al. 2020

Cell Commun Signal

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“…Anti-Flag antibody (M2) is from Sigma 69 . Anti-MEK5 antibody (AB3184) is from EMD Millipore 22 , anti-lamin A/C (636) 70 , ERK5 (C-7) 26 and myc (9E10) 71 antibodies are from Santa Cruz and anti-MEK1/2 72 , phospho-T359 RSK 73 and total RSK 74 from Cell Signaling Technology. Secondary antibodies were from BioRad 40,41 .…”

Section: Methodsmentioning

confidence: 99%

Paradoxical activation of the protein kinase-transcription factor ERK5 by ERK5 kinase inhibitors

et al. 2020

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The dual protein kinase-transcription factor, ERK5, is an emerging drug target in cancer and inflammation, and small-molecule ERK5 kinase inhibitors have been developed. However, selective ERK5 kinase inhibitors fail to recapitulate ERK5 genetic ablation phenotypes, suggesting kinase-independent functions for ERK5. Here we show that ERK5 kinase inhibitors cause paradoxical activation of ERK5 transcriptional activity mediated through its unique C-terminal transcriptional activation domain (TAD). Using the ERK5 kinase inhibitor, Compound 26 (ERK5-IN-1), as a paradigm, we have developed kinase-active, drug-resistant mutants of ERK5. With these mutants, we show that induction of ERK5 transcriptional activity requires direct binding of the inhibitor to the kinase domain. This in turn promotes conformational changes in the kinase domain that result in nuclear translocation of ERK5 and stimulation of gene transcription. This shows that both the ERK5 kinase and TAD must be considered when assessing the role of ERK5 and the effectiveness of anti-ERK5 therapeutics. 1 1234567890():,;E xtracellular signal-regulated kinase 5 (ERK5, also known as Big MAP Kinase or BMK1) 1,2 is a member of the mitogenactivated protein kinase (MAPK) family, which also includes ERK1/2 3 , the JNKs 4 and the p38 kinases 5 . Like ERK1/2, ERK5 is the effector kinase of a three-tiered MAPK pathway, comprising MEKK2 and MEKK3 (the MKKKs), MEK5 (MKK) and finally ERK5 (MAPK). ERK5 is encoded by the MAPK7 gene and includes an N-terminal kinase domain that shares 50% identity with ERK2 1,2 . However, it also contains a large, unique C-terminal extension that includes a nuclear localisation signal (NLS) and a transcriptional activation domain (TAD) (Fig. 1a) 6 . The ERK5 pathway is activated by mitogens 7 , agonists of the Tolllike receptor-2 8 and cellular stresses 9 . Upon cellular stimulation, activated MEK5 phosphorylates the TEY motif in the ERK5 activation-loop, leading to activation of its kinase domain 10 . The ERK5 C-terminus also becomes auto-phosphorylated and promotes ERK5 translocation from the cytosol to the nucleus 11,12 , where ERK5 has been shown to interact with MEF2 transcription factors such as MEF2D 7,13,14 . The C-terminus can also be regulated by other protein kinases, including ERK1/2 15 and CDK1 16,17 , which phosphorylate C-terminal residues independently of ERK5 kinase activity. Thus, the C-terminus mediates NATURE COMMUNICATIONS | https://doi.

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“…The human genome contains 13 let-7 family member genes, which are distributed in different genomic loci and codify for 9 mature miRNAs 41 . Let-7 expression is downregulated in many cancers, such as lung, breast, pancreatic cancer, and melanoma and in many cancer-associated clinical conditions like cholestasis 42 . Moreover, downregulation of let-7 expression correlates with poor survival in lung cancer 43 , ovarian cancer 44 , and head and neck SCC patients 45 .…”

Section: Meg3mentioning

confidence: 99%

The role of noncoding RNAs in epithelial cancer

et al. 2020

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Regulatory noncoding RNAs (ncRNAs) are a class of RNAs transcribed by regions of the human genome that do not encode for proteins. The three main members of this class, named microRNA, long noncoding RNA, and circular RNA play a key role in the regulation of gene expression, eventually shaping critical cellular processes. Compelling experimental evidence shows that ncRNAs function either as tumor suppressors or oncogenes by participating in the regulation of one or several cancer hallmarks, including evading cell death, and their expression is frequently deregulated during cancer onset, progression, and dissemination. More recently, preclinical and clinical studies indicate that ncRNAs are potential biomarkers for monitoring cancer progression, relapse, and response to cancer therapy. Here, we will discuss the role of noncoding RNAs in regulating cancer cell death, focusing on those ncRNAs with a potential clinical relevance. Facts • Many of the genetic and epigenetics alterations in human cancers are found in noncoding regions of the DNA. How can we integrate preclinical findings to select the best regulatory ncRNA for clinical studies?

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H19 potentiates let-7 family expression through reducing PTBP1 binding to their precursors in cholestasis

Cited by 38 publications

References 56 publications

LncRNAH19 improves insulin resistance in skeletal muscle by regulating heterogeneous nuclear ribonucleoprotein A1

LncRNAH19 improves insulin resistance in skeletal muscle by regulating heterogeneous nuclear ribonucleoprotein A1

Paradoxical activation of the protein kinase-transcription factor ERK5 by ERK5 kinase inhibitors

The role of noncoding RNAs in epithelial cancer

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