Hsp70 is a novel posttranscriptional regulator of gene expression that binds and stabilizes selected mRNAs containing AU-rich elements.

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TitleHsp70 is a novel posttranscriptional regulator of gene expression that binds and stabilizes selected mRNAs containing AU-rich elements.
Publication TypeJournal Article
Year of Publication2013
AuthorsKishor, A, Tandukar, B, Ly, YV, Toth, EA, Suarez, Y, Brewer, G, Wilson, GM
JournalMol Cell Biol
Volume33
Issue1
Pagination71-84
Date Published2013 Jan
ISSN1098-5549
Keywords3' Untranslated Regions, AU Rich Elements, Binding Sites, Cyclooxygenase 2, Gene Expression Regulation, HeLa Cells, HL-60 Cells, HSP70 Heat-Shock Proteins, Humans, Molecular Chaperones, Protein Structure, Tertiary, RNA Processing, Post-Transcriptional, RNA Stability, RNA, Messenger, Vascular Endothelial Growth Factor A
Abstract

The AU-rich elements (AREs) encoded within many mRNA 3' untranslated regions (3'UTRs) are targets for factors that control transcript longevity and translational efficiency. Hsp70, best known as a protein chaperone with well-defined peptide-refolding properties, is known to interact with ARE-like RNA substrates in vitro. Here, we show that cofactor-free preparations of Hsp70 form direct, high-affinity complexes with ARE substrates based on specific recognition of U-rich sequences by both the ATP- and peptide-binding domains. Suppressing Hsp70 in HeLa cells destabilized an ARE reporter mRNA, indicating a novel ARE-directed mRNA-stabilizing role for this protein. Hsp70 also bound and stabilized endogenous ARE-containing mRNAs encoding vascular endothelial growth factor (VEGF) and Cox-2, which involved a mechanism that was unaffected by an inhibitor of its protein chaperone function. Hsp70 recognition and stabilization of VEGF mRNA was mediated by an ARE-like sequence in the proximal 3'UTR. Finally, stabilization of VEGF mRNA coincided with the accumulation of Hsp70 protein in HL60 promyelocytic leukemia cells recovering from acute thermal stress. We propose that the binding and stabilization of selected ARE-containing mRNAs may contribute to the cytoprotective effects of Hsp70 following cellular stress but may also provide a novel mechanism linking constitutively elevated Hsp70 expression to the development of aggressive neoplastic phenotypes.

DOI10.1128/MCB.01275-12
Alternate JournalMol. Cell. Biol.
PubMed ID23109422
PubMed Central IDPMC3536313
Grant ListR01 CA102428 / CA / NCI NIH HHS / United States
R01 CA102428 / CA / NCI NIH HHS / United States
R01 CA52443 / CA / NCI NIH HHS / United States