© 2003 by Oxford University Press
© 2003 Oxford University Press
ARTICLE |
Interaction of Retroviral Tax Oncoproteins With Tristetraprolin and Regulation of Tumor Necrosis Factor-
Expression
Affiliations of authors: Biologie cellulaire et moléculaire, Faculté Universitaire des Sciences Agronomiques, Gembloux, Belgium (JCT, LL, DC, CD, AB, RK, LW); Institut de Biologie Moléculaire et de Médecine, Université Libre de Bruxelles, Gosselies, Belgium (VK); Faculté de médicine vétérinaire, Université de Liège, Liège, Belgium (AV); Office of Clinical Research and Laboratory of Signal Transduction, National Institute of Environmental Health Sciences, Research Triangle Park, NC (WSL, PJB); Deutsches Krebsforschungszentrum, Heidelberg, Germany (JCJ); Department of Pathology and Laboratory Medicine, Texas A & M University, College Station, TX (JCT, LRB); Department of Microbiology and Molecular Cell Biology, Eastern Virginia Medical School, Norfolk, VA (OJS).
Correspondence to: Luc Willems, PhD, Biologie cellulaire et moléculaire, Faculté Universitaire des Sciences Agronomiques de Gembloux, 13 avenue Maréchal Juin, B5030 Gembloux, Belgium (e-mail: willems.l{at}fsagx.ac.be)
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-
(TNF-), 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- 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- expression. This observation is of importance for the cell transformation process induced by leukemogenic retroviruses, because TNF- overexpression plays a central role in pathogenesis.
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