Reference : Interaction of retroviral Tax oncoproteins with tristetraprolin and regulation of tum...
Scientific journals : Article
Human health sciences : Oncology
Life sciences : Biochemistry, biophysics & molecular biology
Interaction of retroviral Tax oncoproteins with tristetraprolin and regulation of tumor necrosis factor-alpha expression.
Twizere, Jean-Claude mailto [Université de Liège - ULiège > Gembloux Agro-Bio Tech > Gembloux Agro-Bio Tech >]
Kruys, Veronique [> > > >]
Lefebvre, Laurent [> > > >]
Vanderplasschen, Alain mailto [Université de Liège - ULiège > > Immunologie et vaccinologie >]
Collete, Delphine [> > > >]
Debacq, Christophe [> > > >]
Lai, Wi S [> > > >]
Jauniaux, Jean-Claude [> > > >]
Bernstein, Lori R [> > > >]
Semmes, O John [> > > >]
Burny, Arsene [> > > >]
Blackshear, Perry J [> > > >]
Kettmann, Richard mailto [Université de Liège - ULiège > Gembloux Agro-Bio Tech > Gembloux Agro-Bio Tech >]
Willems, Luc mailto [Université de Liège - ULiège > > GIGA-Research - Gembloux Agro-Bio Tech >]
Journal of the National Cancer Institute
Oxford University Press
Yes (verified by ORBi)
[en] Animals ; Cattle ; DNA, Complementary/analysis ; DNA-Binding Proteins ; Gene Expression Regulation, Neoplastic ; Gene Products, tax/metabolism ; Human T-lymphotropic virus 1 ; Humans ; Immediate-Early Proteins/genetics/metabolism ; Leukemia Virus, Bovine ; Microscopy, Confocal ; Mutation ; Neoplasms/metabolism/virology ; Plasmids ; Polymerase Chain Reaction ; Precipitin Tests ; Transfection ; Tristetraprolin ; Tumor Necrosis Factor-alpha/metabolism ; Up-Regulation ; beta-Galactosidase/metabolism
[en] BACKGROUND: The Tax oncoproteins are transcriptional regulators of viral expression involved in pathogenesis induced by complex leukemogenic retroviruses (or delta-retroviruses, i.e., primate T-cell leukemia viruses and bovine leukemia virus). To better understand the molecular pathways leading to cell transformation, we aimed to identify cellular proteins interacting with Tax. METHODS: We used a yeast two-hybrid system to identify interacting cellular proteins. Interactions between Tax and candidate interacting cellular proteins were confirmed by glutathione S-transferase (GST) pulldown assays, co-immunoprecipitation, and confocal microscopy. Functional interactions between Tax and one interacting protein, tristetraprolin (TTP), were assessed by analyzing the expression of tumor necrosis factor-alpha (TNF-alpha), which is regulated by TTP, in mammalian cells (HeLa, D17, HEK 293, and RAW 264.7) transiently transfected with combinations of intact and mutant Tax and TTP. RESULTS: We obtained seven interacting cellular proteins, of which one, TTP, was further characterized. Tax and TTP were found to interact specifically through their respective carboxyl-terminal domains. The proteins colocalized in the cytoplasm in a region surrounding the nucleus of HeLa cells. Furthermore, coexpression of Tax was associated with nuclear accumulation of TTP. TTP is an immediate-early protein that inhibits expression of TNF-alpha at the post-transcriptional level. Expression of Tax reverted this inhibition, both in transient transfection experiments and in stably transfected macrophage cell lines. CONCLUSION: Tax, through its interactions with the TTP repressor, indirectly increases TNF-alpha expression. This observation is of importance for the cell transformation process induced by leukemogenic retroviruses, because TNF-alpha overexpression plays a central role in pathogenesis.
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