Department of Neurology, University of Alabama at Birmingham, Birmingham, AL 35294-3300, USA.
J Neurooncol. 2013 Jun;113(2):195-205. doi: 10.1007/s11060-013-1112-8. Epub 2013 Mar 25.
Malignant gliomas rely on the production of certain critical growth factors including VEGF, interleukin (IL)-6 and IL-8, to fuel rapid tumor growth, angiogenesis, and treatment resistance. Post-transcriptional regulation through adenine and uridine-rich elements of the 3' untranslated region is one mechanism for upregulating these and other growth factors. In glioma cells, we have shown that the post-transcriptional machinery is optimized for growth factor upregulation secondary to overexpression of the mRNA stabilizer, HuR. The negative regulator, tristetraprolin (TTP), on the other hand, may be suppressed because of extensive phosphorylation. Here we test that possibility by analyzing the phenotypic effects of a mutated form of TTP (mt-TTP) in which 8 phosphoserine residues were converted to alanines. We observed a significantly enhanced negative effect on growth factor expression in glioma cells at the post-transcriptional and transcriptional levels. The protein became stabilized and displayed significantly increased antiproliferative effects compared to wild-type TTP. Macroautophagy was induced with both forms of TTP, but inhibition of autophagy did not affect cell viability. We conclude that glioma cells suppress TTP function through phosphorylation of critical serine residues which in turn contributes to growth factor upregulation and tumor progression.
恶性神经胶质瘤依赖于某些关键生长因子的产生，包括 VEGF、白细胞介素 (IL)-6 和 IL-8，以促进肿瘤的快速生长、血管生成和治疗耐药性。通过 3'非翻译区的腺嘌呤和尿嘧啶丰富元件的转录后调控是上调这些和其他生长因子的一种机制。在神经胶质瘤细胞中，我们已经表明，由于 mRNA 稳定剂 HuR 的过度表达，转录后机制被优化用于生长因子的上调。另一方面，负调节剂 tristetraprolin (TTP) 可能由于广泛的磷酸化而受到抑制。在这里，我们通过分析突变形式的 TTP（mt-TTP）的表型效应来检验这种可能性，其中 8 个磷酸丝氨酸残基被转化为丙氨酸。我们观察到在转录后和转录水平上，TTP 在神经胶质瘤细胞中对生长因子表达的负效应显著增强。与野生型 TTP 相比，该蛋白变得稳定，并显示出显著增强的抗增殖作用。两种形式的 TTP 都诱导了巨自噬，但自噬的抑制并不影响细胞活力。我们得出结论，神经胶质瘤细胞通过关键丝氨酸残基的磷酸化抑制 TTP 功能，这反过来又有助于生长因子的上调和肿瘤的进展。
