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- Title
Interaction of retroviral Tax oncoproteins with tristetraprolin and regulation of tumor necrosis factor-alpha expression.
- Authors
Twizere, Jean-Claude; Kruys, Véronique; Lefèbvre, Laurent; Vanderplasschen, Alain; Collete, Delphine; Debacq, Christophe; Lai, Wi S.; Jauniaux, Jean-Claude; Bernstein, Lori R.; Semmes, O. John; Burny, Arsène; Blackshear, Perry J.; Kettmann, Richard; Willems, Luc; Kruys, Véronique; Lefèbvre, Laurent; Burny, Arsène
- Abstract
<bold>Background: </bold>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.<bold>Methods: </bold>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.<bold>Results: </bold>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.<bold>Conclusion: </bold>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.
- Subjects
TUMOR necrosis factors; MACROPHAGES; RETROVIRUSES; ONCOGENIC viruses; GLYCOPROTEINS; BOVINE leukosis
- Publication
JNCI: Journal of the National Cancer Institute, 2003, Vol 95, Issue 24, p1846
- ISSN
0027-8874
- Publication type
journal article
- DOI
10.1093/jnci/djg118