Malignant gliomas are highly aggressive tumors of the central nervous system that rely on production of growth factors for tumor progression. Vascular endothelial growth factor (VEGF), interleukin-8 (IL-8), and tumor necrosis factor-α, for example, are up-regulated in these tumors to promote angiogenesis and proliferation. RNA stability, mediated through adenine and uridine-rich elements (ARE) in the 3′ untranslated region, is a critical control point for regulating these growth factors. RNA half-life is predominantly governed by a balance between stabilizing and destabilizing factors that bind to ARE. We have previously shown that the stabilizing factor HuR is overexpressed in malignant gliomas and linked to RNA stabilization of angiogenic growth factors. Here, we report that the destabilizing factor tristetraprolin (TTP) is also ubiquitously expressed in primary malignant glioma tissues and cell lines. In contrast to benign astrogliotic tissues, however, the protein was hyperphosphorylated, with evidence implicating the p38/mitogen-activated protein kinase (MAPK) pathway. Conditional overexpression of TTP as a transgene in malignant glioma cells led to RNA destabilization of IL-8 and VEGF and down-regulation of protein production. Analysis of in vivo RNA binding indicated a shift of mRNA toward ectopic TTP and away from endogenous HuR. This biochemical phenotype was associated with a decrease in cell proliferation, loss of cell viability, and apoptosis. We postulate that hyperphosphorylation of TTP via p38/MAPK promotes progression of malignant gliomas by negatively regulating its RNA destabilizing function. ©2008 American Association for Cancer Research.