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10. Regulation of HuR structure and function by dihydrotanshinone-I

Author

Lal, Preet, primary, Cerofolini, Linda, additional, D’Agostino, Vito Giuseppe, additional, Zucal, Chiara, additional, Fuccio, Carmelo, additional, Bonomo, Isabelle, additional, Dassi, Erik, additional, Giuntini, Stefano, additional, Di Maio, Danilo, additional, Vishwakarma, Vikalp, additional, Preet, Ranjan, additional, Williams, Sha Neisha, additional, Fairlamb, Max S., additional, Munk, Rachel, additional, Lehrmann, Elin, additional, Abdelmohsen, Kotb, additional, Elezgarai, Saioa R., additional, Luchinat, Claudio, additional, Novellino, Ettore, additional, Quattrone, Alessandro, additional, Biasini, Emiliano, additional, Manzoni, Leonardo, additional, Gorospe, Myriam, additional, Dixon, Dan A., additional, Seneci, Pierfausto, additional, Marinelli, Luciana, additional, Fragai, Marco, additional, and Provenzani, Alessandro, additional

Published
2017
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11. Regulation of HuR structure and function by dihydrotanshinone-I

Author

Ranjan Preet, Luciana Marinelli, Pierfausto Seneci, Emiliano Biasini, Linda Cerofolini, Ettore Novellino, Vito Giuseppe D'Agostino, Dan A. Dixon, Vikalp Vishwakarma, Isabelle Bonomo, Carmelo Fuccio, Max S. Fairlamb, Sha Neisha Williams, Marco Fragai, Preet Lal, Saioa R. Elezgarai, Rachel Munk, Alessandro Provenzani, Kotb Abdelmohsen, Chiara Zucal, Myriam Gorospe, Erik Dassi, Danilo Di Maio, Claudio Luchinat, Elin Lehrmann, Stefano Giuntini, Leonardo Manzoni, Alessandro Quattrone, Lal, Preet, Cerofolini, Linda, D'Agostino, Vito Giuseppe, Zucal, Chiara, Fuccio, Carmelo, Bonomo, Isabelle, Dassi, Erik, Giuntini, Stefano, Maio, Danilo Di, Vishwakarma, Vikalp, Preet, Ranjan, Williams, Sha Neisha, Fairlamb, Max S., Munk, Rachel, Lehrmann, Elin, Abdelmohsen, Kotb, Elezgarai, Saioa R., Luchinat, Claudio, Novellino, Ettore, Quattrone, Alessandro, Biasini, Emiliano, Manzoni, Leonardo, Gorospe, Myriam, Dixon, Dan A., Seneci, Pierfausto, Marinelli, Luciana, Fragai, Marco, and Provenzani, Alessandro

Subjects
0301 basic medicine, Magnetic Resonance Spectroscopy, Xenograft Model Antitumor Assay, Immunoprecipitation, Protein Conformation, Protein Domain, 3' Untranslated Region, Protein domain, ELAV-Like Protein 1, Mice, Neurologic Mutant, RNA-binding protein, Biology, Molecular Dynamics Simulation, 03 medical and health sciences, Mice, Neurologic Mutants, Protein Domains, Phenanthrene, dihydrotanshinone I, Genetics, Animals, Humans, Point Mutation, RNA, Messenger, Furans, 3' Untranslated Regions, Molecular Biology, Ribonucleoprotein, AU-rich element, AU Rich Elements, Three prime untranslated region, Animal, Quinones, RNA, Phenanthrenes, Xenograft Model Antitumor Assays, Antineoplastic Agents, Phytogenic, Cell biology, AU Rich Element, 030104 developmental biology, HuR, Human
Abstract

The Human antigen R protein (HuR) is an RNA-binding protein that recognizes U/AU-rich elements in diverse RNAs through two RNA-recognition motifs, RRM1 and RRM2, and post-transcriptionally regulates the fate of target RNAs. The natural product dihydrotanshinone-I (DHTS) prevents the association of HuR and target RNAs in vitro and in cultured cells by interfering with the binding of HuR to RNA. Here, we report the structural determinants of the interaction between DHTS and HuR and the impact of DHTS on HuR binding to target mRNAs transcriptome-wide. NMR titration and Molecular Dynamics simulation identified the residues within RRM1 and RRM2 responsible for the interaction between DHTS and HuR. RNA Electromobility Shifts and Alpha Screen Assays showed that DHTS interacts with HuR through the same binding regions as target RNAs, stabilizing HuR in a locked conformation that hampers RNA binding competitively. HuR ribonucleoprotein immunoprecipitation followed by microarray (RIP-chip) analysis showed that DHTS treatment of HeLa cells paradoxically enriched HuR binding to mRNAs with longer 3′UTR and with higher density of U/AU-rich elements, suggesting that DHTS inhibits the association of HuR to weaker target mRNAs. In vivo, DHTS potently inhibited xenograft tumor growth in a HuR-dependent model without systemic toxicity.

Published
2017

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