Charcot-Marie-Tooth disease (CMT) is a length-dependent peripheral neuropathy. The aminoacyl-tRNA synthetases constitute the largest protein family implicated in CMT. Aminoacyl-tRNA synthetases are predominantly cytoplasmic, but are also present in the nucleus. Here we show that a nuclear function of tyrosyl-tRNA synthetase (TyrRS) is implicated in a Drosophila model of CMT. CMT-causing mutations in TyrRS induce unique conformational changes, which confer capacity for aberrant interactions with transcriptional regulators in the nucleus, leading to transcription factor E2F1 hyperactivation. Using neuronal tissues, we reveal a broad transcriptional regulation network associated with wild-type TyrRS expression, which is disturbed when a CMT-mutant is expressed. Pharmacological inhibition of TyrRS nuclear entry with embelin reduces, whereas genetic nuclear exclusion of mutant TyrRS prevents hallmark phenotypes of CMT in the Drosophila model. These data highlight that this translation factor may contribute to transcriptional regulation in neurons, and suggest a therapeutic strategy for CMT.
Background: Drug resistance is a major cause of cancer treatment failure. Most cancer therapies involve multiple agents, to overcome it. Compounds that exhibit strong anti-tumor effect without damaging normal cells are more and more in the focus of research. Chemotherapeutic drugs, combining different moieties and functional groups in one molecule, can modulate different regulatory pathways in the cell and thus reach the higher efficacy than the agents, which affect only one cellular process. Methods: We tested the effect of recently synthesized ferrocene-containing camphor sulfonamide DK-164 on two breast cancer and one breast non-cancer cell lines. The cytotoxic effects were evaluated using the standard MTT-dye reduction and clonogenic assays. The apoptotic or autophagic effects were evaluated by Annexin v binding or LC3 puncta formation assays respectively. Cell cycle arrest was determined using flow cytometry. Western blot and immunofluorescent analyses were used to estimate the localization and cellular distribution of key regulatory factors NFκB and p53. Results: Compound DK-164 has well pronounced cytotoxicity greater to cancer cells (MDA-MB-231 and MCF-7) compared to non-cancerous (MCF-10A). IC50 of the substance caused a cell cycle arrest in G1 phase and induced apoptosis up to 24 hours in both tumor cells, although being more pronounced in MCF-7, a functional p53 cell line. Treatment with IC50 concentration of the compound provoked autophagy in both tumor lines but is better pronounced in the more aggressive cancer line (MDA-MB-231). Conclusion: The tested compound DK-164 showed promising properties as a potential therapeutic agent.
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