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Papers In Press, published online ahead of print June 7, 2002
J. Biol. Chem, 10.1074/jbc.M112398200
Submitted on December 27, 2001
Revised on May 28, 2002
Accepted on June 7, 2002
Biochemistry and Medical Biotechnology, University Federico II, Naples 80131
Corresponding Author: scala{at}dbbm.unina.it
Tat protein of the Human Immunodeficiency Virus type-1 (HIV-1) plays a critical role in the regulation of viral transcription and replication. In addition, Tat regulates the expression of a variety of cellular genes and could account for AIDS-associated diseases, including Kaposi’s Sarcoma and non-Hodgkin’s lymphoma, by interfering with cellular processes such as proliferation, differentiation and apoptosis. The molecular mechanisms underlying the pleiotropic activities of Tat may include the generation of functional heterodimers of Tat with cellular proteins. By screening a human B-lymphoblastoid cDNA library in the Yeast Two-Hybrid System we identified E2F-4, a member of E2F family of transcription factors, as a Tat-binding protein. The interaction between Tat and E2F-4 was confirmed by GST pull-down experiments performed with cellular extracts as well as with in vitro translated E2F-4. The physical association of Tat and E2F-4 was confirmed by in vivo binding experiments where Tat:E2F-4 heterodimers were recovered from Jurkat cells by immunoprecipitation and immunoblotting. By using plasmids expressing mutant forms of Tat and E2F-4, the domains involved in Tat-E2F-4 interaction were identified as the regions encompassing aa 1-49 of Tat and aa 1-184 of E2F-4. Tat:E2F-4 complexes were shown to bind to E2F cis regions with increased efficiency compared to E2F-4 alone and to mediate the activity of E2F-dependent promoters, including HIV-1 LTR and Cyclin A. The data point to Tat as an adapter protein that recruits cellular factors, such as E2F4, to exert its multiple biological activities.
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