title: Mutant tristetraprolin: a potent inhibitor of malignant glioma cell growth.
abstract: 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.
authors.affiliation: Department of Neurology, University of Alabama at Birmingham, Birmingham, AL 35294-3300, USA. easuswam@uab.edu
authors.forename: Esther A
authors.initials: EA
authors.lastname: Suswam
authors.forename: John J
authors.initials: JJ
authors.lastname: Shacka
authors.forename: Kiera
authors.initials: K
authors.lastname: Walker
authors.forename: Liang
authors.initials: L
authors.lastname: Lu
authors.forename: Xuelin
authors.initials: X
authors.lastname: Li
authors.forename: Ying
authors.initials: Y
authors.lastname: Si
authors.forename: Xiaowen
authors.initials: X
authors.lastname: Zhang
authors.forename: Lei
authors.initials: L
authors.lastname: Zheng
authors.forename: L Burt
authors.initials: LB
authors.lastname: Nabors
authors.forename: Heping
authors.initials: H
authors.lastname: Cao
authors.forename: Peter H
authors.initials: PH
authors.lastname: King
mesh_terms: D020413:3' Untranslated Regions; D017209:Apoptosis; D015153:Blotting, Western; D001932:Brain Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D049109:Cell Proliferation; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D005910:Glioma / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D047468:Immunoprecipitation; D015850:Interleukin-6 / Q000378:metabolism; D016209:Interleukin-8 / Q000378:metabolism; D009154:Mutation / Q000235:genetics*; D010766:Phosphorylation; D020871:RNA Stability / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D051816:Tristetraprolin / Q000235:genetics* / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: D020413:3' Untranslated Regions; D015850:Interleukin-6; D016209:Interleukin-8; D012333:RNA, Messenger; D051816:Tristetraprolin; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A