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Molecular Biology and Genetics |
Induces Angiogenic Factor Up-Regulation in Malignant Glioma Cells
Birmingham Veterans Affairs Medical Center, Birmingham, Alabama 35233 [L. B. N., E. S., Y. H., X. Y., P. H. K.], and Departments of Neurology [L. B. N., P. H. K.], Clinical Pharmacology [M. J. J.], and Physiology and Biophysics [P. H. K.], University of Alabama at Birmingham, Birmingham, Alabama 35294-0007
Malignant glioma (MG) cells up-regulate angiogenic factor expression in response to different extracellular signals such as hypoxia and cytokines. This up-regulation in turn promotes angiogenesis and tumor progression. Posttranscriptional gene regulation has been implicated as one mechanism for this tumor response, and we have previously shown that HuR, a protein associated with RNA stabilization, is overexpressed in MGs (L. B. Nabors et al., Cancer Res., 61: 2154–2161, 2001). Here, we demonstrate a marked up-regulation (RNA and protein) of tumor necrosis factor 
(TNF-), interleukin 8, and, to a lesser extent, vascular endothelial growth factor in U251 glioma cells after stimulation with TNF-. RNA kinetic studies indicated that TNF- induced the stabilization of all three transcripts. Using a luciferase reporter assay, we demonstrate that the AU-rich elements (AREs) in the 3'-untranslated region of these genes significantly contribute to this posttranscriptional regulation. UV cross-linking and immunoprecipitation with glioma extracts indicate that HuR binds to all three AREs. When HuR is overexpressed in glioma cells, there is enhanced RNA stabilization of all three angiogenic factor transcripts with a concomitant increase in mRNA and protein expression (up to 7-fold). These findings indicate that TNF- up-regulates angiogenic factor expression in MG cells and that RNA stabilization, via the AREs in the 3'-untranslated region, contributes to this up-regulation.
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