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Title:
Dihydrotanshinone-I interferes with the RNA-binding activity of HuR affecting its post-transcriptional function | Scientific Reports
Description:
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.
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nature portfolio ndei/xhoi-digested pet-42a vector il-6/stat3/nf-kb signaling pathways privacy policy nature author information authors axonomix research project translational inflammation research p38/mk2-driven exchange advertising research biochemical high-throughput screening solutions 0/ reprints salvia miltiorrhiza bunge pre-formed protein-rna complex post-transcriptional regulons coordinate hur-mediated post-transcriptional inhibition adenine-uridine-rich elements dimethyl-substituted cyclohexene ring mrna-stabilizing factor hur nucleo-cytoplasmic cell fractionation aromatic methyl-substituted ring involving post-transcriptional regulation post-transcriptional gene regulation mediated post-transcriptional regulation development fluorescence intensity/cell population q-rt-pcr analysis post-transcriptionally modulate cytokines full size image human breast carcinoma predicted post-transcriptional regulation post-transcriptionally modulate tnf key pro-inflammatory genes pcmv-hur recombinant vector50 defined trans-acting factors puno-htnfa/3′utrδare plasmids mda-mb-231 adhesion properties pre-mrna processing events28 anti-inflammatory agents allowed au-rich element au-rich elements hur-rna complex formation puno1-htnfa vector digested pkcbeta/hur/vegf pathway specific protein-rna interactions m1_m2-rna complex formation inter-domain linker region recombinant puno-htnfa/3′utr
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headline:Dihydrotanshinone-I interferes with the RNA-binding activity of HuR affecting its post-transcriptional function
description: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 (Kiâ=â3.74â±â1.63ânM). 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.
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headline:Dihydrotanshinone-I interferes with the RNA-binding activity of HuR affecting its post-transcriptional function
description: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 (Kiâ=â3.74â±â1.63ânM). 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.
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