Posttranscriptional gene regulation by the RNA binding protein HuR in two disease models : allergic asthma and breast cancer
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[ACCESS RESTRICTED TO THE UNIVERSITY OF MISSOURI AT AUTHOR'S REQUEST.] The RNA binding protein HuR binds to the AU-rich (ARE) regions of labile mRNAs, such as proto-oncogenes, stabilizing their mRNA and facilitating their translation into protein. HuR has been described to control genes in multiple areas of the acquired capabilities model of cancer and has been hypothesized to be a tumor-maintenance gene, allowing for cancers to proliferate once they are established. In additional to controlling genes involved in cancer, HuR also regulates genes involved in the immune system including. We investigated the role of HuR in two disease models: triple-negative breast cancer and allergic asthma. To understand the role of HuR in both cancer and allergic asthma we generated novel overexpression and underexpression models. Unexpectedly breast cancer tumors overexpressing HuR grew significantly slower than control tumors. Tumors overexpressing HuR had fewer blood vessels implicating HuR's role in angiogenesis. The putative mechanism seems to be an anti-angiogenic effect by increasing expression of TSP1 but also surprisingly, down-regulating VEGF, a target which HuR normally increases. Additionally, we generated and used lentiviral shRNA targeting HuR, transgenic mice overexpressing HuR in CD4+ T cells and a HuR conditional knockout (KO) mouse to understand the role of HuR in Th2 polarization. We show that the Th2 master transcription factor GATA-3, as well as IL-4 and IL-13 are regulated at the level of mRNA stability by HuR. Surprisingly, Th2 polarized cells from homozygous HuR knockout mice showed increased IL-2, IL-4 and IL-13 expression at both mRNA and protein levels but no changes in GATA-3 or IFNgamma. Despite these alterations in Th2 cytokine levels, HuR conditional KO mice have similar allergic airway inflammation as control mice.
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