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Originally published In Press as doi:10.1074/jbc.M112398200 on June 7, 2002
J. Biol. Chem., Vol. 277, Issue 35, 31448-31458, August 30, 2002
Physical and Functional Interaction of HIV-1 Tat with E2F-4,
a Transcriptional Regulator of Mammalian Cell Cycle*
Concetta
Ambrosino ,
Camillo
Palmieri ,
Antimina
Puca§,
Francesca
Trimboli§,
Marco
Schiavone§,
Francesco
Olimpico§,
Maria R.
Ruocco§,
Francesca
di Leva§,
Mario
Toriello§,
Ileana
Quinto §,
Salvatore
Venuta , and
Giuseppe
Scala §¶
From the Department of Clinical and Experimental
Medicine, Medical School, University of Catanzaro, 88100 Catanzaro,
Italy, and § Department of Biochemistry and Medical
Biotechnology, Medical School, University "Federico II," 80131 Naples, Italy
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 amino acids 1-49 of Tat and amino acids 1-184 of E2F-4.
Tat·E2F-4 complexes were shown to bind to E2F cis-regions with increased efficiency compared with E2F-4 alone and to mediate the
activity of E2F-dependent promoters including HIV-1 long
terminal repeat and cyclin A. The data point to Tat as
an adaptor protein that recruits cellular factors such as E2F-4 to
exert its multiple biological activities.
*
This work was supported in part by grants from
Associazione Italiana per la Ricerca sul Cancro (AIRC), Istituto
Superiore di Sanita` (ISS) for AIDS project, Telethon, and Ministero
dell'Istruzione dell'Universitè e delle Ricerce (MIUR).The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
¶
To whom correspondence should be addressed. E-mail:
scala@unicz.it.
Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.

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Copyright © 2002 by the American Society for Biochemistry and Molecular Biology.
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