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HuR's role in gemcitabine efficacy: an exception or opportunity?

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Abstract Over the next few years, research teams will focus on, and millions of dollars will be spent on, sorting through cancer genomes. Undoubtedly, ‘druggable’ targets and events will be discovered that will improve our understanding and, hopefully, treatment of cancer. Highlighting an alternative to this ‘genome‐centric’ approach, this review will further explore an underappreciated mechanism of gene expression regulation, posttranscription mRNA:protein interactions. A key molecule involved in this mode of gene regulation is HuR and we have shown that HuR levels and HuR cellular distribution can predict how pancreatic cancer patients responded to the standard of care chemotherapy (i.e., gemcitabine). HuR regulates post‐transcriptional processes through: (1) association with specific mRNA cargos with ARE‐rich sequences and (2) stress‐induced increased cytoplasmic protein levels. Over multiple laboratories and diverse tumor types, it has been shown that HuR supports tumor survival through its regulation of tumor‐promoting transcripts such as VEGF. In this article, we will highlight a recent discovery that this potent post‐transcriptional gene regulatory mechanism has an impact on a common chemotherapeutic, gemcitabine. Specifically, we have identified the mechanism by which HuR can regulate a key gemcitabine metabolic enzyme, deoxycytidine kinase. We will use this example to explore and hypothesize the functional roles that HuR may have on anticancer drug therapies. We will survey novel high throughput global gene expression analysis tools to discover novel HuR targets. Future multidisciplinary approaches focused on HuR biology will provide critical events and ‘druggable’ targets in cancer that large‐scale genomic sequencing efforts will miss. WIREs RNA 2011 2 435–444 DOI: 10.1002/wrna.62 This article is categorized under: RNA Interactions with Proteins and Other Molecules > Protein–RNA Recognition RNA Interactions with Proteins and Other Molecules > Protein–RNA Interactions: Functional Implications RNA in Disease and Development > RNA in Disease RNA Methods > RNA Analyses In Vitro and In Silico

Strategy to study drug response from an HuR'ocentric perpsective. The flow chart simplifies a sequential molecular biology–systems biology approach of studying a drug response that includes rigorous validation. In this experimental scenario, HuR:mRNA interactions are in the cytoplasm.

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RNA Interactions with Proteins and Other Molecules > Protein–RNA Interactions: Functional Implications
RNA Interactions with Proteins and Other Molecules > Protein–RNA Recognition
RNA Methods > RNA Analyses In Vitro and In Silico
RNA in Disease and Development > RNA in Disease

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