Conditional Knockout of the RNA-Binding Protein HuR in CD4+ T Cells Reveals a Gene Dosage Effect on Cytokine Production

Gubin, Matthew M.; Techasintana, Patsharaporn; Magee, Joseph; Dahm, Garrett M.; Calaluce, Robert; Martindale, Jennifer L.; Whitney, Maryln S.; Franklin, Craig L.; Besch-Williford, Cindy; Hollingsworth, John W.; Abdelmohsen, Kotb; Gorospe, Myriam; Atasoy, Ulus

doi:10.2119/molmed.2013.00127

Cited by 31 publications

(35 citation statements)

References 64 publications

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“…Interestingly, mice with conditional HuR deletion in a cell/tissue-specific manner are viable as observed in the GI tract (41,42), lung epithelium (43,44), brain (45), T-cells (46), and macrophages (47), and suggested that deletion of HuR in GI cancer cells would be feasible. Our findings demonstrate that PDA and CRC HuR-null cells are able to establish and grow in vitro , however, when cells become stressed with chemotoxic agents (Supplementary Fig.…”

Section: Discussionmentioning

confidence: 99%

CRISPR Knockout of the HuR Gene Causes a Xenograft Lethal Phenotype

Lal

Cheung

Zarei

et al. 2017

Molecular Cancer Research

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Pancreatic ductal adenocarcinoma (PDA) is the third leading cause of cancer related deaths in the U.S., while colorectal cancer (CRC) is the third most common cancer. The RNA binding protein HuR (ELAVL1), supports a pro-oncogenic network in gastrointestinal (GI) cancer cells through enhanced HuR expression. Using a publically available database, HuR expression levels were determined to be increased in primary PDA and CRC tumor cohorts as compared to normal pancreas and colon tissues, respectively. CRISPR/Cas9 technology was successfully used to delete the HuR gene in both PDA (MIA PaCa-2 and Hs 766T) and CRC (HCT116) cell lines. HuR deficiency has a mild phenotype, in vitro, as HuR-deficient MIA PaCa-2 (MIA.HuR-KO(−/−)) cells had increased apoptosis when compared to isogenic wild-type (MIA.HuR-WT(+/+)) cells. Using this isogenic system, mRNAs were identified that specifically bound to HuR and were required for transforming a 2D culture into 3D (i.e., organoids). Importantly, HuR-deficient MIA PaCa-2 and Hs 766T cells were unable to engraft tumors in vivo compared to control HuR-proficient cells, demonstrating a unique xenograft lethal phenotype. While not as a dramatic phenotype, CRISPR knockout HuR HCT116 colon cancer cells (HCT.HuR-KO(−/−)) showed significantly reduced in vivo tumor growth compared to controls (HCT.HuR-WT(+/+)). Finally, HuR deletion affects KRAS activity and controls a subset of pro-oncogenic genes. Implications The work reported here supports the notion that targeting HuR is a promising therapeutic strategy to treat GI malignancies.

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Section: Discussionmentioning

confidence: 99%

CRISPR Knockout of the HuR Gene Causes a Xenograft Lethal Phenotype

Lal

Cheung

Zarei

et al. 2017

Molecular Cancer Research

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“…HuR flox/flox mice were generated as described previously (28,51). 8 -10-week-old control (HuR flox/flox ) mice and HuR KO mice (OX40-cre HuR flox/flox ) were used.…”

Section: Animalsmentioning

confidence: 99%

The RNA-binding protein HuR contributes to neuroinflammation by promoting C-C chemokine receptor 6 (CCR6) expression on Th17 cells

Chen

Martindale

Cramer

et al. 2017

Journal of Biological Chemistry

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In both multiple sclerosis and experimental autoimmune encephalomyelitis (EAE), the C-C chemokine receptor 6 (CCR6) is critical for pathogenic T helper 17 (Th17) cell migration to the central nervous system (CNS). Whereas many cytokines and their receptors are potently regulated via post-transcriptional mechanisms in response to various stimuli, how CCR6 expression is post-transcriptionally regulated in Th17 cells is unknown. Here, using RNA-binding protein HuR conditional knock-out (KO) and wild-type (WT) mice, we present evidence that HuR post-transcriptionally regulates CCR6 expression by binding to and stabilizing mRNA and by promoting CCR6 translation. We also found that HuR down-regulates several microRNA expressions, which could target the 3'-UTR of Ccr6 mRNA for decay. Accordingly, knock-out of HuR reduced CCR6 expression on Th17 cells and impaired their migration to CNS compared with the response of WT Th17 cells and thereby ameliorated EAE. Together, these findings highlight how HuR contributes to Th17 cell-mediated autoimmune neuroinflammation and support the notion that targeting HuR might be a potential therapeutic intervention for managing autoimmune disorders of the CNS.

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“…206 • ELAVL1 HuR mouse models ELAVL1-knockout mice display embryonic lethality, thus, a number of conditional HuRknockout or conditional HuR-transgenic mice have been developed and largely for the study of the immune system. [207][208][209][210] These models have not been evaluated in cancer studies and may offer opportunities to study the effect specific immune cells as affected by HuR on cancer. It may be preferable to use the conditional knockout models as opposed to transgenic models to avoid opposite effects of HuR due to overexpression since HuR is abundantly expressed ubiquitous gene.…”

Section: • Zfp36δare Micementioning

confidence: 99%

Hallmarks of cancer and AU‐rich elements

Khabar

2016

WIREs RNA

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Post‐transcriptional control of gene expression is aberrant in cancer cells. Sustained stabilization and enhanced translation of specific mRNAs are features of tumor cells. AU‐rich elements (AREs), cis‐acting mRNA decay determinants, play a major role in the posttranscriptional regulation of many genes involved in cancer processes. This review discusses the role of aberrant ARE‐mediated posttranscriptional processes in each of the hallmarks of cancer, including sustained cellular growth, resistance to apoptosis, angiogenesis, invasion, and metastasis. WIREs RNA 2017, 8:e1368. doi: 10.1002/wrna.1368For further resources related to this article, please visit the WIREs website.

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Conditional Knockout of the RNA-Binding Protein HuR in CD4+ T Cells Reveals a Gene Dosage Effect on Cytokine Production

Cited by 31 publications

References 64 publications

CRISPR Knockout of the HuR Gene Causes a Xenograft Lethal Phenotype

CRISPR Knockout of the HuR Gene Causes a Xenograft Lethal Phenotype

The RNA-binding protein HuR contributes to neuroinflammation by promoting C-C chemokine receptor 6 (CCR6) expression on Th17 cells

Hallmarks of cancer and AU‐rich elements

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