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10.1038/srep16478

http://scihub22266oqcxt.onion/10.1038/srep16478
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suck abstract from ncbi


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pmid26553968
      Sci+Rep 2015 ; 5 (ä): 16478
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  • Dihydrotanshinone-I interferes with the RNA-binding activity of HuR affecting its post-transcriptional function #MMPMID26553968
  • D'Agostino VG ; Lal P ; Mantelli B ; Tiedje C ; Zucal C ; Thongon N ; Gaestel M ; Latorre E ; Marinelli L ; Seneci P ; Amadio M ; Provenzani A
  • Sci Rep 2015[Nov]; 5 (ä): 16478 PMID26553968 show ga
  • Post-transcriptional regulation is an essential determinant of gene expression programs in physiological and pathological conditions. HuR is a RNA-binding protein that orchestrates the stabilization and translation of mRNAs, critical in inflammation and tumor progression, including tumor necrosis factor-alpha (TNF). We identified the low molecular weight compound 15,16-dihydrotanshinone-I (DHTS), well known in traditional Chinese medicine practice, through a validated high throughput screening on a set of anti-inflammatory agents for its ability to prevent HuR:RNA complex formation. We found that DHTS interferes with the association step between HuR and the RNA with an equilibrium dissociation constant in the nanomolar range in vitro (Ki?=?3.74?±?1.63?nM). In breast cancer cell lines, short term exposure to DHTS influences mRNA stability and translational efficiency of TNF in a HuR-dependent manner and also other functional readouts of its post-transcriptional control, such as the stability of selected pre-mRNAs. Importantly, we show that migration and sensitivity of breast cancer cells to DHTS are modulated by HuR expression, indicating that HuR is among the preferential intracellular targets of DHTS. Here, we disclose a previously unrecognized molecular mechanism exerted by DHTS, opening new perspectives to therapeutically target the HuR mediated, post-transcriptional control in inflammation and cancer cells.
  • |Breast Neoplasms [MESH]
  • |Cell Line, Tumor [MESH]
  • |Cytoplasm/metabolism [MESH]
  • |Drug Resistance, Neoplasm/genetics [MESH]
  • |ELAV-Like Protein 1/genetics/*metabolism [MESH]
  • |Female [MESH]
  • |Furans [MESH]
  • |Gene Expression Regulation/drug effects [MESH]
  • |Humans [MESH]
  • |MCF-7 Cells [MESH]
  • |Phenanthrenes/*pharmacology/toxicity [MESH]
  • |Polyribosomes/metabolism [MESH]
  • |Protein Binding/drug effects [MESH]
  • |Quinones [MESH]
  • |RNA Processing, Post-Transcriptional/*drug effects [MESH]
  • |RNA, Messenger/*genetics/*metabolism [MESH]
  • |RNA-Binding Proteins/metabolism [MESH]


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